TY - JOUR
AU - Packer,, Milton
AB - Abstract Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of serious heart failure events, even though SGLT2 is not expressed in the myocardium. This cardioprotective benefit is not related to an effect of these drugs to lower blood glucose, promote ketone body utilization or enhance natriuresis, but it is linked statistically with their action to increase haematocrit. SGLT2 inhibitors increase both erythropoietin and erythropoiesis, but the increase in red blood cell mass does not directly prevent heart failure events. Instead, erythrocytosis is a biomarker of a state of hypoxia mimicry, which is induced by SGLT2 inhibitors in manner akin to cobalt chloride. The primary mediators of the cellular response to states of energy depletion are sirtuin-1 and hypoxia-inducible factors (HIF-1α/HIF-2α). These master regulators promote the cellular adaptation to states of nutrient and oxygen deprivation, promoting mitochondrial capacity and minimizing the generation of oxidative stress. Activation of sirtuin-1 and HIF-1α/HIF-2α also stimulates autophagy, a lysosome-mediated degradative pathway that maintains cellular homoeostasis by removing dangerous constituents (particularly unhealthy mitochondria and peroxisomes), which are a major source of oxidative stress and cardiomyocyte dysfunction and demise. SGLT2 inhibitors can activate SIRT-1 and stimulate autophagy in the heart, and thereby, favourably influence the course of cardiomyopathy. Therefore, the linkage between erythrocytosis and the reduction in heart failure events with SGLT2 inhibitors may be related to a shared underlying molecular mechanism that is triggered by the action of these drugs to induce a perceived state of oxygen and nutrient deprivation. SGLT2 inhibitors, Autophagy, Hypoxia-inducible factors, Sirtuin-1, Cardioprotection 1. Introduction In patients with Type 2 diabetes, sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of serious heart failure events, specifically the risk of hospitalization for heart failure, and often cardiovascular death.1 The benefit is most apparent in patients with a reduced ejection fraction.2 Furthermore, dapagliflozin reduced the risk of cardiovascular death and hospitalizations for heart failure in patients with established systolic heart failure, including those without diabetes.3 The mechanism of this cardioprotective benefit is unknown. 2. Mechanisms cannot explain SGLT2 inhibitor-mediated cardioprotection It has been challenging to explain how SGLT2 inhibitors act to slow the evolution and progression of the cardiomyopathic process since SGLT2 is not present in the normal or failing heart.4,5 SGLT2 is primarily expressed in the proximal renal tubule, where it mediates glucose reabsorption.6 However, it is not clear how an action on the kidney to promote glycosuria might mitigate injurious processes in the myocardium and reduce the risk of serious heart failure events. 2.1 SGLT2 inhibitors do not produce cardioprotective effects by their action to lower glycated haemoglobin Hyperglycaemia can produce deleterious effects on the heart,7 but the magnitude of the blood glucose-lowering effect of SGLT2 inhibitors is modest, and in the large-scale trials with these drugs, the benefit on the reduction in heart failure hospitalizations was not related to the decline in glycated haemoglobin.1,2 Drugs that exert greater antihyperglycaemic effects than SGLT2 inhibitors do not reduce the risk of serious heart failure events.8 Furthermore, the favourable effect of SGLT2 inhibitors on heart failure is seen even in patients without Type 2 diabetes.3 Hence, the antihyperglycaemic action of SGLT2 inhibitors cannot explain the ability of these drugs to reduce the evolution and progression of cardiomyopathy. 2.2 SGLT2 inhibitors do not produce cardioprotective effects as a result of their action to promote sodium excretion SGLT2 inhibitors block sodium reabsorption in the proximal renal tubule, and some have hypothesized that the reduction in the risk of heart failure events is related to this natriuretic effect, leading to a decrease in intravascular or interstitial volume.9,10 SGLT2 inhibitors can promote a short-term increase in urine volume in patients with acutely decompensated heart failure11; however, their effect on urinary sodium excretion and plasma volume in stable patients is modest and often transient.12–15 Furthermore, SGLT2 inhibitors have not potentiated the effects of loop diuretics in clinical trials or cohort studies,3,16 and they have not produced a meaningful immediate decline in circulating levels of natriuretic peptides,3,17 as would be expected from a drug that acts primarily as a diuretic. Slowing of the rate of rise of natriuretic peptides seen during long-term treatment is likely the result of—rather than a contributing factor to—a favourable action of these drugs on left ventricular remodelling.3,18 Moreover, SGLT2 inhibitors have not ameliorated symptoms of pulmonary or systemic congestion in clinical trials of patients with chronic heart failure.17 Importantly, the use of SGLT2 inhibitors reduces the risk of cardiovascular death, whereas intensification of diuretic therapy has been associated with an increased mortality rate.19 2.3 SGLT2 inhibitors do not produce cardioprotective effects by increasing the delivery of fuel or oxygen to the myocardium In contrast to other antihyperglycaemic drugs, SGLT2 inhibitors promote ketogenesis through a combined action to enhance both gluconeogenesis and fatty acid oxidation.20–22 Some have proposed that the resulting increase in circulating ketone bodies provides an efficient fuel for the failing heart.23,24 However, ketonaemia is an established feature of patients with heart failure25 and the failing myocardium already utilizes ketone bodies as a preferred fuel26,27—in the absence of a SGLT2 inhibitor.26,27 Although the infusion of beta-hydroxybutyrate produces short-term increases in cardiac contractility and heart rate,28 SGLT2 inhibitors do not produce these hemodynamic changes in clinical trials. Furthermore, SGLT2 inhibitors have not consistently enhanced ketone body consumption by the myocardium under experimental conditions.21,29–32 Importantly, the increases in ATP production and cardiac efficiency seen following SGLT2 inhibition are not related to enhanced ketone body metabolism.30,31 An intriguing feature of SGLT2 inhibitors in clinical trials has been their action to increase the synthesis of erythropoietin and thereby increase red blood cell mass.33 Theoretically, if the failing heart were hypoxic, erythrocytosis could increase oxygen delivery to the stressed myocardium, which might be particularly important in patients with coronary artery disease. However, there is no evidence for insufficient oxygen availability in hearts under states of hemodynamic stress.34 Furthermore, in a large-scale trial, the magnitude of the benefits of SGLT2 inhibitors in heart failure did not depend on whether patients had underlying ischaemic heart disease; patients with an ischaemic aetiology did not benefit preferentially from SGLT2 inhibition.3 Finally, when erythrocytosis is produced by erythropoietin-mimetic agents, the increase in red blood cell mass does not lead to favourable effects on cardiovascular death or heart failure hospitalizations in patients with chronic heart failure, even though the haematocrit was subnormal at the start of treatment.35 3. Erythrocytosis provides a statistical and molecular clue to the mechanism leading to the reduction in heart failure events with SGLT2 inhibitors Although the failing heart does not benefit from the increase in oxygen delivery produced by an expanded red blood cell mass, the erythrocytosis seen with SGLT2 inhibitors may nevertheless be an indicator of the molecular events that underlie their cardioprotective benefits. When statistical mediation analyses are carried out in the large-scale trials with SGLT2 inhibitors, the increase in red blood cell counts emerges as the single most important variable to predict the decreased risk of cardiovascular death and heart failure hospitalizations produced by SGLT2 inhibitors.36,37 This finding suggests that erythrocytosis is closely associated with the molecular pathways involved in cardioprotection, i.e. the enhanced erythropoiesis and the reduction in serious heart failure events are linked statistically not because the expanded red blood cell mass improves cardiac oxygenation, but because erythrocytosis and the cardioprotective effects have a shared underlying molecular mechanism. 4. Why do SGLT2 inhibitors stimulate erythropoietin? The concordant and counterbalancing effects of hypoxia-inducible factors and sirtuin-1 The primary regulators of erythropoietin synthesis are hypoxia-inducible factors (HIFs) that transactivate the gene for erythropoietin. Two inducible isoforms—HIF-1α and HIF-2α—are up-regulated by hypoxia or by drugs that mimic hypoxia under normoxic conditions (e.g. cobalt chloride).38,39 HIF-1α and HIF-2α appear to activate the same downstream genes, but they do so differently in different tissues and under different conditions. Typically, HIF-1α promotes the transcription of genes encoding metabolic enzymes, transporters, and mitochondrial proteins that decrease oxygen utilization,40,41 whereas HIF-2α is the isoform that is the primary stimulus for erythropoietin synthesis.39 Importantly, HIFs respond not only to oxygen deprivation but also to changes in caloric balance and to levels of glycaemia.42,43 Both isoforms act to lower blood glucose, and in turn, glucose deprivation suppresses both HIF-1α and HIF-2α.43,44 It is therefore noteworthy that HIF-2α mediates adaptation to hypoglycaemia,45 whereas HIF-1α primarily activates genes typically triggered by hypoxia41,46—except for the synthesis of erythropoietin. Another critical component of the cellular response to hypoxia in cardiomyocytes is up-regulation of sirtuin-1 (SIRT1),42–44 a redox-sensitive nicotinamide adenine dinucleotide-dependent enzyme that deacetylates target proteins, many of which are responsible for the maintenance of blood glucose and cellular homoeostasis. As in the case for HIFs, the activity of SIRT1 is exquisitely responsive to nutrient deprivation as well as hypoxia47,48; a primary function of SIRT1 is to maintain blood glucose levels during states of hypoglycaemic stress.49 Additionally, SIRT1 acts to mute cellular stress and exerts protective effects in a broad range of organs (including the heart),50–52 explaining why SIRT1 may be the mechanistic link between caloric restriction and organismal longevity.53 4.1 Counterbalancing effects of HIF-1α and SIRT1 Interestingly, the actions of HIFs and SIRT1 oppose and counterbalance each other in many ways. With respect to glucose and lipid homoeostasis, HIF-1α switches cells from oxidative to glycolytic metabolism (thus allowing for the maintenance of ATP levels under hypoxic conditions), and HIF-2α acts to inhibit gluconeogenesis.43,44 These effects—together with an action to inhibit fatty acid oxidation—explain why both isoforms act to lower blood glucose and to suppress ketone body formation.54–57 However, SIRT1 signalling counteracts these effects on glucose and lipid metabolism. SIRT1 promotes glycogenolysis, gluconeogenesis, and fatty acid oxidation,58 while inhibiting glycolysis,59 and SIRT1 activates the rate-limiting step for ketone body production.60 As a result of these actions, SIRT1 supports blood glucose and promotes ketogenesis, thus directly opposing the metabolic actions of HIF-1α. At the same time, as part of its action to mute oxygen consumption, HIF-1α impairs the biogenesis of mitochondria,61 whereas SIRT1 promotes the formation of healthy mitochondria and regulates mitochondrial quality control by facilitating the disposal of dysfunctional or damaged organelles.62 HIF-1α and SIRT1 also appear to exert counterbalancing effects on inflammation. SIRT1 interacts directly with NF-κB to suppress its activation, thus suppressing myocardial and vascular inflammation.63,64 In contrast, increased HIF-1α signalling promotes M1 polarization and enhances proinflammatory pathways in macrophages,65–68 and NF-κB promotes the up-regulation of HIF-1α.68,69 4.2 Concordant and mutually reinforcing effects of HIF-2α and SIRT1 Interestingly, HIF-2α—the primary isoform responsible for erythropoiesis—has actions on inflammation that align with those of SIRT1 but are opposite to those of HIF-1α, i.e. HIF-2α mutes the inflammatory response that underlies insulin resistance in obesity.70 Importantly, the oppositional effects of HIF-1α and HIF-2α in macrophages are paralleled by their counterbalancing actions on inflammatory processes in the heart. Cardiac activation of HIF-1α promotes inflammation,71,72 whereas increased expression of HIF-2α in cardiomyocytes preserves mitochondrial integrity and prevents injury in experimental ischaemia.73,74 Activation of HIF-2α (when produced by inhibitors of its degradation) attenuates experimental cardiac inflammation, fibrosis, and adverse remodelling.75–78 The parallelism between many (but not all) of the actions of SIRT1 and those of HIF-2α is intriguing, since SIRT1 increases the expression of HIF-2α, and in turn, HIF-2α (and erythropoietin, the protein product of HIF-2α transactivation) augments SIRT1 signalling in cardiomyocytes and other cell types.79–82 The mutually stimulating components of the SIRT1/HIF-2α/erythropoietin axis mitigate the response to and the adverse consequences of disease states that promote cardiomyocyte stress and injury. 5. Coordinated actions of HIFs and SIRT1 on autophagic clearance of organellar sources of oxidative stress Although HIFs and SIRT1 have counterbalancing or concordant effects under varying conditions, these master regulators act in a coordinated manner to stimulate the cellular housekeeping process of autophagy. Autophagy is a lysosomally mediated degradative pathway that maintains cellular homoeostasis by removing dangerous constituents and recycling cellular components. States of nutrient and oxygen deprivation are the primary triggers of autophagy,83 and the degradation of cellular elements provides a supply of nutrients that can maintain cellular ATP during low-energy states. Importantly, autophagy is also stimulated by oxidative stress,84 and in response, the process of cellular self-digestion clears the cytoplasm of damaged organelles (especially mitochondria and peroxisomes) that are the major sources of reactive oxygen species and cellular dysfunction in cardiomyocytes.85 Yet, the housekeeping functions of autophagy are critically depressed in the myocardium of subjects with type 2 diabetes or with heart failure and play an important in promoting cardiac injury and accelerating cardiac dysfunction.86–88 Conversely, experimental induction of autophagy has favourable effects to minimize ischaemia-reperfusion injury, mitigate left ventricular remodelling and retard the evolution of cardiomyopathy related to diverse causes.89–93 Hypoxia-inducible factors and SIRT1 are important stimuli for the enhancement of autophagic flux; in doing so, their activation plays a protective role in preserving cellular health and viability and preventing maladaptive remodelling following cardiac injury.94–98 Enhanced activity of HIF-1α and SIRT1 in cardiomyocytes promotes the autophagic clearance of damaged mitochondria, a process known as mitophagy.97,98 Chronic hypoxia and ischaemic preconditioning in the myocardium stimulate HIF-1α and autophagy in parallel, and mitophagy is (in part) HIF-1α-dependent.97,99 Additionally, the activation of SIRT1 stimulates HIF-2α,79,80 which leads to enhanced clearance of damaged or dysfunctional peroxisomes, a process known as pexography.100,101 Both SIRT1 and HIF-1α also act to directly preserve organellar function and integrity.62,102 Mitochondria and peroxisomes are the major sources of reactive oxygen species and the injurious effects of oxidative stress in cardiomyocytes. Thus, the coordinated activation of HIFs and SIRT1—the key elements of the cellular response to oxygen and nutrient deprivation—is poised to ameliorate the organellar stress and cellular dysfunction seen in a broad range of myocardial disorders. 6. Role of HIF and SIRT1 signalling in the cardiac adaptation to stress During embryonic development, HIF-1α protects the embryo from intrauterine hypoxia, but at the time of birth, normoxia suppresses HIFs as the heart switches from anaerobic to aerobic metabolism. The expression of HIFs remains low as long as the heart remains healthy, but if oxygen tension in the adult heart declines, HIFs are activated to facilitate oxygen delivery.103 These transcription factors not only enhance the synthesis of erythropoietin but they also induce angiogenesis, and the development of a nurturing micro-circulation can increase oxygenation of hypertrophied or ischaemic myocardium. For these reasons, activation of HIF-1α and HIF-2α has been shown to ameliorate ischaemia-reperfusion injury in the heart,76,104–107 whereas suppression of HIF-1α causes decompensation of experimental pressure overload or ischaemic states, which may be related to inadequate vascularization.108 These observations demonstrate that activation of HIF-1α can have cardioprotective effects, at least in the short-term when oxygen tension is rapidly lowered, as in states of acute ischaemia. However, several investigations have raised doubts about the cardioprotective benefits of HIF-1α when its activation is marked and sustained for long periods of time. HIF-1α maintains myocardial energy levels during hypoxia by shifting from oxidative to glycolytic metabolism; however, such an effect might limit cardiac performance, since glycolysis represents an inefficient mechanism of consuming oxygen in order to generate ATP.109 Moreover, HIF-1α acts to impair mitochondrial biogenesis, thereby further limiting the generation of ATP needed to maintain cardiac performance.108 Finally, HIF-1α (when activated by non-hypoxic stimuli) may play an important role in promoting inflammation in cardiomyocytes.71,72 As a result of these mechanisms, marked, sustained, and isolated activation of HIF-1α leads to an impairment of cardiac performance. Specifically, prolonged pharmacological inhibition of the prolyl hydroxylases that is responsible for HIF-1α degradation (which stabilize HIF-1α at high levels) leads to worsening of cardiac function.110 Similarly, marked activation produced by genetic overexpression of HIF-1α results in cardiomyopathy.111 6.1 Modulating influence of SIRT1 on the induction and actions of HIF-1α and HIF-2α during hypoxia or treatment with hypoxia-mimetic agents However, experimental conditions that cause such extreme and isolated activation of HIF-1α may not be clinically relevant. During hypoxia or treatment with hypoxia-mimetic agents (e.g. cobalt chloride), the induction of HIFs is accompanied by coactivation of SIRT1 in the heart, liver, and endothelium.82,112,113 The effects of SIRT1 on HIF-1α vary with the cell type,114–117 but SIRT1 agonism inhibits HIF-1α in cardiomyocytes,118 and SIRT1 opposes many of the actions of HIF-1α. SIRT1 counteracts the inhibitory effects of HIF-1α on oxidative metabolism, gluconeogenesis, and ketogenesis and on mitochondrial biogenesis and ATP production57–61; additionally, SIRT1 mutes activation of the inflammasome, thus negating the proinflammatory actions of HIF-1α.63–69 SIRT1 also activates HIF-2α, further offsetting HIF-1α-triggered inflammatory pathways.70–74 Regardless of these counterbalancing effects on metabolism and inflammation, the coactivation of SIRT1 with HIFs promotes autophagy, and thus, acts to remove potentially dangerous constituents, thereby reducing oxidative and endoplasmic reticular stress and attenuating the resulting inflammatory response that leads to cellular dysfunction and death. Therefore, coordinated stimulation of HIFs and SIRT1 not only promotes erythropoiesis but it also mediates meaningful cardioprotective effects, thereby explaining the finding of a statistical linkage between erythrocytosis and the reduction in serious heart failure events.36,37 Not surprisingly, the activities of HIF-2α and SIRT1 are reduced in various forms of cardiomyopathy. Suppression of these master regulators accelerates cardiac injury, and their induction ameliorates cardiomyocyte loss and dysfunction.74,119–124 7. Effects of SGLT2 inhibitors on HIFs, SIRT1, and autophagy and their link to cardioprotection Because SGLT2 acts as a sensor of energy overabundance, there is an inverse relationship between SGLT2 and the activity of enzymes and transcription factors that are triggered by nutrient and oxygen deprivation. States of low-oxygen tension cause simultaneous down-regulation of SGLT2 but up-regulation of HIF-1α,125 whereas high levels of renal tubular glucose promote the expression of SGLT2 but reduce the expression of SIRT1.126 7.1 Effect of SGLT2 inhibitors on SIRT1 and HIFs Given these inverse relationships, it is not surprising that pharmacological inhibition of SGLT2 leads to activation of HIFs and SIRT1 (Figure 1). SGLT2 inhibitors have been shown to stimulate SIRT1 in a broad range of tissues, including the heart, kidney, and liver.20,126–129 SIRT1-mediated activation of HIF-2α in the kidney can promote erythropoietin production in the interstitial fibroblasts that are the primary site of synthesis79,130; prolonged increases in HIF-2α activity enhances the growth of these specialized cells.131 Additionally, activation of HIF-2α in the liver (also related to SIRT1 signalling) can contribute importantly to the production of erythropoietin.132 The likelihood of SIRT1-mediated hepatic synthesis undermines the assumption that erythropoietin synthesis provoked by SGLT2 inhibitors is strictly limited to the renal medulla. Although these drugs have been hypothesized to provoke medullary hypoxia as a consequence of an action to increase oxygen consumption in distal tubular sites,133,134 this response remains controversial. Furthermore, the isoform induced by SGLT2 inhibitors in the outer renal medulla in models of hypoxia/ischaemia appears to be HIF-1α, which is not the primary driver of erythropoietin synthesis.135 Figure 1 Open in new tabDownload slide SGLT2 inhibitors may exert cardioprotective effects by inducing a nutrient- and oxygen-deprivation transcriptional paradigm. SGLT2, sodium-glucose co-transporter 2; SIRT1, sirtuin-1; HIF-1α, hypoxia-inducible factor isoform 1α; HIF-2α, hypoxia-inducible factor isoform 2α; AMPK, 5′-adenosine monophosphate-activated protein kinase. Figure 1 Open in new tabDownload slide SGLT2 inhibitors may exert cardioprotective effects by inducing a nutrient- and oxygen-deprivation transcriptional paradigm. SGLT2, sodium-glucose co-transporter 2; SIRT1, sirtuin-1; HIF-1α, hypoxia-inducible factor isoform 1α; HIF-2α, hypoxia-inducible factor isoform 2α; AMPK, 5′-adenosine monophosphate-activated protein kinase. SGLT2 inhibitors have been reported to up-regulate HIF-1α in non-diabetic renal injury,135,136 but down-regulate the isoform in the diabetic kidney136; yet, the effect of these drugs on HIF-1α in the heart has not yet been examined. If the activation of HIF-1α by SGLT2 inhibitors is confined to renal tissues, these drugs might not cause increases in cardiac HIF-1α that could excite inflammatory changes in the myocardium. Alternatively, if SGLT2 inhibitors were to be shown to enhance the activation of HIF-1α in the heart, any potential that HIF-1α would produce deleterious effects in cardiomyocytes might be negated by concomitant activation of SIRT1. In fact, it seems likely that, during treatment with SGLT2 inhibitors, the action of these drugs to promote SIRT1 signalling dominate and supersede any effects that might be related to the activation of HIF-1α. SGLT2 inhibition augments gluconeogenesis, fatty acid oxidation, and ketogenesis,20,21,29,137,138 but these effects are explicable only by the actions of SIRT1,58–60 and cannot be ascribed to HIF-1α.54–57 Additionally, SGLT2 inhibitors modify macrophage polarization to promote an anti-inflammatory phenotype,139,140 and they mute inflammation in the myocardium.141 These actions are consistent with the activation of SIRT1, and they cannot be explained by HIF-1α.63–68 Interestingly, anti-inflammatory changes in macrophage polarization are also seen with other hypoxia-mimetics (i.e. cobalt), but interestingly, these stimulate SIRT1 and HIF-2α in addition to HIF-1α.82,142 Finally, SGLT2 inhibitors promote mitochondrial biogenesis,21 an effect that reflects the actions of SIRT1 rather than those of HIF-1α, because the latter suppresses the formation of these organelles.61,62 7.2 Effect of SGLT2 inhibitors on other transcription factors and master regulators that can influence autophagic flux It is possible that SGLT2 inhibitors may promote autophagy by mechanisms in addition to enhanced signalling through SIRT1 and HIFs. Activation of the Akt/mTOR pathway suppresses autophagic flux, and SGLT2 inhibitors may inhibit Akt/mTOR,143 thereby enhancing autophagy.144 Furthermore, SGLT2 inhibitors activate another energy deprivation sensor, adenosine monophosphate-activated protein kinase (AMPK),29,141,143,145–148 which also acts to stimulate autophagy. The activity of both Akt/mTOR and AMPK in cardiomyocytes is sensitive to hypoxia.149,150 It is, therefore, noteworthy that other hypoxia-mimetics (e.g. cobalt chloride) promote autophagy, an effect is accompanied by simultaneously inhibition of AKT/mTOR and activation of AMPK.151 There is considerable interdependence between SIRT1 and AMPK; these two enzymes can often mutually activate each other, and they share many common downstream targets152; in contrast, the effects of HIF-1α to promote autophagy are not mediated by AMPK.153 Nevertheless, it seems unlikely that AMPK plays a dominant role in mediating the effects of most members of the SGLT2 inhibitor class of drugs since AMPK acts to suppress gluconeogenesis, ketogenesis, and erythrocytosis154–156; this profile of effects is opposite to that produced by most SGLT2 inhibitors. 7.3 The intriguing paradox of nutrient- and oxygen-deprivation signalling and autophagy stimulation in the absence of SGLT2 expression How can SGLT2 inhibitors to promote SIRT1 signalling in the heart if SGLT2 is not expressed in the myocardium? SGLT2 inhibitors have profound effects in many organs that do not express SGLT2 or bind SGLT2 inhibitors,4,5,157 including cardiac and skeletal muscle, liver, and adipose depots.20,158–161 How does inhibition of SGLT2 influence the structure and function of these tissues? SGLT2 inhibition induces loss of calories in the urine, which (by reducing glucose levels in the tissues) triggers a fasting-like transcriptional paradigm in organs throughout the body.143 Activation of SIRT1 is a cornerstone of the organismal response to starvation (since SIRT1 serves to maintain blood glucose),49 and thus, glycosuria (and its effects on environmental glucose) activates SIRT1 systemically; this activation occurs in all tissues, regardless of whether they express SGLT2.20 Additionally, SGLT2 may act as a central sensor for the energy state of the organism, and thus, suppression of its activity can stimulate SIRT1 even if there is no actual loss of calories in the urine.125,126 By virtue of either or both mechanisms, nutrient-deprivation signalling provoked by SGLT2 inhibition can activate HIFs and AMPK (in addition to SIRT1) in diverse organs. The concerted systemic activation of multiple master regulators involved in nutrient- and oxygen-deprivation signalling likely underlies the ability of empagliflozin, dapagliflozin, and canagliflozin to promote autophagic flux in many organs, including the heart,145,162–164 both in diabetic and in non-diabetic rodent models. Such an action may explain why SGLT2 inhibitors act to reduce oxidative stress, normalize mitochondrial structure and function, and mute the activity of the NLRP3 inflammasome in the stressed myocardium.21,141,162,165 Enhanced autophagy may also account for the effect of SGLT2 inhibitors to ameliorate ischaemia-reperfusion injury and post-infarction remodelling and to minimize micro-vascular dysfunction, hypertrophy and fibrosis, enhance contractile performance, and ameliorate the course of experimental cardiomyopathy.21,92,93,158,159,165,166 7.4 Influence of SIRT1/HIF-1α/HIF-2α signalling on sodium transporters and intracellular sodium concentration It has recently been hypothesized that SGLT2 inhibitors may reduce the risk of serious heart failure events by an effect to inhibit ion channels or exchangers that mediate an increase in intracellular sodium, with its attendant adverse consequences on cardiomyocyte survival.167,168 SGLT2 inhibitors decrease the cytosolic concentration of sodium, but they have not yet been shown to exert an inhibitory action on a specific sodium influx mechanism (i.e. the sodium-hydrogen exchanger).169 It is therefore noteworthy that there exists an inverse relationship between SIRT1/HIF-1α/HIF-2α signalling and many transport mechanisms that mediate sodium influx into cells. SIRT1 overexpression leads to inhibition of the epithelial sodium channel,170 and conversely, overexpression of this channel leads to suppression of SIRT1.171 In parallel, activation of HIF-1α/HIF-2α by the hypoxia-mimetic cobalt leads to inhibition of NHE1,172 which can also be suppressed by activation of AMPK.148 Inhibition of Akt/mTOR signalling causes inhibition of NHE3,173 an effect that is mediated by enhanced autophagy. Therefore, the action of SGLT2 inhibitors to promote nutrient-deprivation signalling may explain the ability of these drugs to lower sodium concentrations in cardiomyocytes, thus contributing to their cardioprotective effects.168 8. Effects of other antihyperglycaemic drugs on HIFs, SIRT1, and autophagy Since autophagy is activated in response to nutrient deprivation, drugs that lower glucose may increase autophagic flux, especially in hyperglycaemic states. Transcriptionally, Type 2 diabetes presents itself as a state of nutrient overabundance, and autophagy is suppressed.174 However, autophagic flux is increased in Type 1 diabetes, suggesting that it is the hyperinsulinaemia of Type 2 diabetes—rather than the hyperglycaemia—that causes down-regulation of autophagy under conditions of glucose intolerance.159 It is therefore noteworthy that insulin itself suppresses autophagic flux, potentially by inhibiting SIRT1 or activating Akt/mTOR signalling.175,176 Consequently, it is difficult to interpret experimental studies that report an effect of antihyperglycaemic drugs on autophagy, since their net result may not only be mediated by an action of glucose-lowering to promote autophagy but by an effect of augmented insulin signalling or other actions to suppress autophagy. Glucagon-like peptide-1 (GLP-1) receptor agonists have been reported to increase autophagy by enhancing activation of AMPK/SIRT1,177,178 but these drugs are not hypoxia-mimetics, and in fact, hypoxia and HIF-1α signalling act to reduce GLP-1 secretion.179,180 Furthermore, GLP-1 receptor agonists promote the secretion of insulin and its suppressive effects on autophagy.176 Analogously, dipeptidyl peptidase 4 inhibitors have been reported to promote autophagy,181 but these drugs also enhance CXCR4 chemokine signalling,182 which decreases autophagic flux.183 Finally, although thiazolidinediones can stimulate AMPK in the heart,184 their actions to promote insulin signalling and sodium influx can increase the risk of serious heart failure events.185 8.1 Effect of metformin on autophagy and its potential interaction with SGLT2 inhibitors In contrast to antihyperglycaemic drugs that act by promoting the secretion or action of insulin, metformin reduces insulin secretion, and the drug enhances autophagy through its ability to function as an agonist of AMPK in diabetic and non-diabetic hearts under stress.91,144,186,187 However, metformin does not appear to have meaningful effects to stimulate SIRT1 or HIFs. Metformin inhibits gluconeogenesis and ketosis188 (which are activated by SIRT1 signalling58 and starvation189), and the drug decreases the haematocrit190—presumably because its stimulatory action on AMPK suppresses HIF-1α—an effect opposite to that of SIRT1.191 Therefore, despite its effect to activate AMPK, metformin does not evoke a state of fasting and hypoxia mimicry or lead to broad-based up-regulation of enzymes and transcription factors that involved in the response to nutrient and oxygen deprivation. Interestingly, there is little evidence that isolated AMPK activation with metformin has favourable effects on the development of heart failure in the clinical setting.192 Therefore, the well-established effects of SGLT2 inhibitors to reduce serious heart failure events may be related to their ability to promote a wide-ranging enhancement of master regulators that are responsible for pattern of fasting and hypoxia mimicry. Nevertheless, it is noteworthy that metformin and SGLT2 inhibitors share an ability to stimulate AMPK in the myocardium. The meaningfulness of this overlap is supported by the observation that the magnitude of the benefit of SGLT2 inhibitors on serious heart failure events in large-scale trials may be attenuated in patients receiving metformin. In the CANVAS trials, canagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure by 36% in patients not receiving metformin, but by only 12% in those receiving metformin (interaction P = 0.03).193 In the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of cardiovascular death by 54% in patients not receiving metformin, but by 29% in those receiving metformin (interaction P = 0.07).194 The benefit in metformin users was still meaningful in the trial that evaluated empagliflozin, but was not in the trial that studied canagliflozin. The greater metformin-related attenuation seen in the CANVAS trials may be related to the greater and more direct AMPK activation produced by canagliflozin than by empagliflozin.146,147 9. Synthesis and clinical implications SGLT2 inhibitors produce erythrocytosis, which has led investigators to propose that these effects increase oxygen delivery to the failing heart. However, it seems more likely that erythrocytosis is a biomarker of an action of SGLT2 inhibitors to induce a hypoxia- and fasting-like transcriptional paradigm, which involves the activation of SIRT-1 and HIF-2α signalling. Transactivation of these downstream mediators not only promotes the synthesis of erythropoietin but it ameliorates cardiomyocyte inflammation and dysfunction, either directly or by stimulating the autophagic clearance of damaged organelles (mitochondria and peroxisomes). This conceptual framework can explain the strong statistical linkage between erythrocytosis and the reduction in serious heart failure events observed in large-scale randomized controlled trials with SGLT2 inhibitors. Conflict of interest: Dr Packer has recently consulted for Abbvie, Actavis, Akcea, Amgen, AstraZeneca, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Johnson & Johnson, NovoNordisk, Pfizer, Sanofi, Synthetic Biologics, and Theravance. References 1 Zelniker TA , Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RHM, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Sabatine MS. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials . Lancet 2019 ; 393 : 31 – 39 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Kato ET , Silverman MG, Mosenzon O, Zelniker TA, Cahn A, Furtado RHM, Kuder J, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Bonaca MP, Ruff CT, Desai AS, Goto S, Johansson PA, Gause-Nilsson I, Johanson P, Langkilde AM, Raz I, Sabatine MS, Wiviott SD. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus . Circulation 2019 ; 139 : 2528 – 2536 . Google Scholar Crossref Search ADS PubMed WorldCat 3 McMurray JJV , Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O’Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde AM; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction . N Engl J Med 2019 ; 381 : 1995 – 2008 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Di Franco A , Cantini G, Tani A, Coppini R, Zecchi-Orlandini S, Raimondi L, Luconi M, Mannucci E. Sodium-dependent glucose transporters (SGLT) in human ischemic heart: a new potential pharmacological target . Int J Cardiol 2017 ; 243 : 86 – 90 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Zhou L , Cryan EV, D’Andrea MR, Belkowski S, Conway BR, Demarest KT. Human cardiomyocytes express high level of Na+/glucose cotransporter 1 (SGLT1) . J Cell Biochem 2003 ; 90 : 339 – 346 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Vallon V , Platt KA, Cunard R, Schroth J, Whaley J, Thomson SC, Koepsell H, Rieg T. SGLT2 mediates glucose reabsorption in the early proximal tubule . J Am Soc Nephrol 2011 ; 22 : 104 – 112 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Ducheix S , Magré J, Cariou B, Prieur X. Chronic O-GlcNAcylation and diabetic cardiomyopathy: the bitterness of glucose . Front Endocrinol 2018 ; 9 : 642 . Google Scholar Crossref Search ADS WorldCat 8 Packer M. Heart failure: the most important, preventable, and treatable cardiovascular complication of type 2 diabetes . Diabetes Care 2018 ; 41 : 11 – 13 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Hallow KM , Helmlinger G, Greasley PJ, McMurray JJV, Boulton DW. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis . Diabetes Obes Metab 2018 ; 20 : 479 – 487 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Dekkers CCJ , Sjöström CD, Greasley PJ, Cain V, Boulton DW, Heerspink H. Effects of the sodium-glucose co-transporter-2 inhibitor dapagliflozin on estimated plasma volume in patients with type 2 diabetes . Diabetes Obes Metab 2019 ; 21 : 2667 – 2673 . Google Scholar Crossref Search ADS PubMed WorldCat 11 Damman K , Beusekamp JC, Boorsma EM, Swart HP, Smilde TDJ, Elvan A, van Eck JWM, Heerspink HJL, Voors AA. Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF) . Eur J Heart Fail 2020 ;doi: 10.1002/ejhf.1713. Google Scholar OpenURL Placeholder Text WorldCat 12 Yasui A , Lee G, Hirase T, Kaneko T, Kaspers S, von Eynatten M, Okamura T. Empagliflozin induces transient diuresis without changing long-term overall fluid balance in Japanese patients with type 2 diabetes . Diabetes Ther 2018 ; 9 : 863 – 871 . Google Scholar Crossref Search ADS PubMed WorldCat 13 Heise T , Jordan J, Wanner C, Heer M, Macha S, Mattheus M, Lund SS, Woerle HJ, Broedl UC. Acute pharmacodynamic effects of empagliflozin with and without diuretic agents in patients with type 2 diabetes mellitus . Clin Ther 2016 ; 38 : 2248 – 2264.e5 . Google Scholar Crossref Search ADS PubMed WorldCat 14 Sha S , Polidori D, Heise T, Natarajan J, Farrell K, Wang SS, Sica D, Rothenberg P, Plum-Mörschel L. Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus . Diabetes Obes Metab 2014 ; 16 : 1087 – 1095 . Google Scholar Crossref Search ADS PubMed WorldCat 15 Ohara K , Masuda T, Murakami T, Imai T, Yoshizawa H, Nakagawa S, Okada M, Miki A, Myoga A, Sugase T, Sekiguchi C, Miyazawa Y, Maeshima A, Akimoto T, Saito O, Muto S, Nagata D. Effects of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on fluid distribution: a comparison study with furosemide and tolvaptan . Nephrology 2019 ; 24 : 904 – 911 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 16 Weeda ER , Cassarly C, Brinton DL, Shirley DW, Simpson KN. Loop diuretic use among patients with heart failure and type 2 diabetes treated with sodium glucose cotransporter-2 inhibitors . J Diabetes Complications 2019 ; 33 : 567 – 571 . Google Scholar Crossref Search ADS PubMed WorldCat 17 Nassif ME , Windsor SL, Tang F, Khariton Y, Husain M, Inzucchi SE, McGuire DK, Pitt B, Scirica BM, Austin B, Drazner MH, Fong MW, Givertz MM, Gordon RA, Jermyn R, Katz SD, Lamba S, Lanfear DE, LaRue SJ, Lindenfeld J, Malone M, Margulies K, Mentz RJ, Mutharasan RK, Pursley M, Umpierrez G, Kosiborod M, Malik AO, Wenger N, Ogunniyi M, Vellanki P, Murphy B, Newman J, Hartupee J, Gupta C, Goldsmith M, Baweja P, Montero M, Gottlieb SS, Costanzo MR, Hoang T, Warnock A, Allen L, Tang W, Chen HH, Cox JM; DEFINE-HF Investigators. Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction: the DEFINE-HF trial . Circulation 2019 ; 140 : 1463 – 1476 . Google Scholar Crossref Search ADS PubMed WorldCat 18 Januzzi JL Jr, Butler J, Jarolim P, Sattar N, Vijapurkar U, Desai M, Davies MJ. Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabetes . J Am Coll Cardiol 2017 ; 70 : 704 – 712 . Google Scholar Crossref Search ADS PubMed WorldCat 19 Damman K , Kjekshus J, Wikstrand J, Cleland JG, Komajda M, Wedel H, Waagstein F, McMurray JJ. Loop diuretics, renal function and clinical outcome in patients with heart failure and reduced ejection fraction . Eur J Heart Fail 2016 ; 18 : 328 – 336 . Google Scholar Crossref Search ADS PubMed WorldCat 20 Swe MT , Thongnak L, Jaikumkao K, Pongchaidecha A, Chatsudthipong V, Lungkaphin A. Dapagliflozin not only improves hepatic injury and pancreatic endoplasmic reticulum stress, but also induces hepatic gluconeogenic enzymes expression in obese rats . Clin Sci 2019 ; 133 : 2415 – 2430 . Google Scholar Crossref Search ADS WorldCat 21 Yurista SR , Silljé HHW, Oberdorf-Maass SU, Schouten EM, Pavez Giani MG, Hillebrands JL, van Goor H, van Veldhuisen DJ, de Boer RA, Westenbrink BD. Sodium-glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction . Eur J Heart Fail 2019 ; 21 : 862 – 873 . Google Scholar Crossref Search ADS PubMed WorldCat 22 Ferrannini E , Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, Mari A, Pieber TR, Muscelli E. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes . Diabetes 2016 ; 65 : 1190 – 1195 . Google Scholar Crossref Search ADS PubMed WorldCat 23 Ferrannini E , Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis . Diabetes Care 2016 ; 39 : 1108 – 1114 . Google Scholar Crossref Search ADS PubMed WorldCat 24 Mudaliar S , Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis . Diabetes Care 2016 ; 39 : 1115 – 1122 . Google Scholar Crossref Search ADS PubMed WorldCat 25 Lommi J , Kupari M, Koskinen P, Näveri H, Leinonen H, Pulkki K, Härkönen M. Blood ketone bodies in congestive heart failure . J Am Coll Cardiol 1996 ; 28 : 665 – 672 . Google Scholar Crossref Search ADS PubMed WorldCat 26 Voros G , Ector J, Garweg C, Droogne W, Van Cleemput J, Peersman N, Vermeersch P, Janssens S. Increased cardiac uptake of ketone bodies and free fatty acids in human heart failure and hypertrophic left ventricular remodeling . Circ Heart Fail 2018 ; 11 : e004953 . Google Scholar Crossref Search ADS PubMed WorldCat 27 Aubert G , Martin OJ, Horton JL, Lai L, Vega RB, Leone TC, Koves T, Gardell SJ, Krüger M, Hoppel CL, Lewandowski ED, Crawford PA, Muoio DM, Kelly DP. The failing heart relies on ketone bodies as a fuel . Circulation 2016 ; 133 : 698 – 705 . Google Scholar Crossref Search ADS PubMed WorldCat 28 Nielsen R , Møller N, Gormsen LC, Tolbod LP, Hansson NH, Sorensen J, Harms HJ, Frøkiær J, Eiskjaer H, Jespersen NR, Mellemkjaer S, Lassen TR, Pryds K, Bøtker HE, Wiggers H. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients . Circulation 2019 ; 139 : 2129 – 2141 . Google Scholar Crossref Search ADS PubMed WorldCat 29 Santos-Gallego CG , Requena-Ibanez JA, San Antonio R, Ishikawa K, Watanabe S, Picatoste B, Flores E, Garcia-Ropero A, Sanz J, Hajjar RJ, Fuster V, Badimon JJ. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics . J Am Coll Cardiol 2019 ; 73 : 1931 – 1944 . Google Scholar Crossref Search ADS PubMed WorldCat 30 Verma S , Rawat S, Ho KL, Wagg CS, Zhang L, Teoh H, Dyck JE, Uddin GM, Oudit GY, Mayoux E, Lehrke M, Marx N, Lopaschuk GD. Empagliflozin increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors . JACC Basic Transl Sci 2018 ; 3 : 575 – 587 . Google Scholar Crossref Search ADS PubMed WorldCat 31 Baker HE , Kiel AM, Luebbe ST, Simon BR, Earl CC, Regmi A, Roell WC, Mather KJ, Tune JD, Goodwill AG. Inhibition of sodium-glucose cotransporter-2 preserves cardiac function during regional myocardial ischemia independent of alterations in myocardial substrate utilization . Basic Res Cardiol 2019 ; 114 : 25 . Google Scholar Crossref Search ADS PubMed WorldCat 32 Abdurrachim D , Teo XQ, Woo CC, Chan WX, Lalic J, Lam CSP, Lee P. Empagliflozin reduces myocardial ketone utilization while preserving glucose utilization in diabetic hypertensive heart disease: a hyperpolarized 13C magnetic resonance spectroscopy study . Diabetes Obes Metab 2019 ; 21 : 357 – 365 . Google Scholar Crossref Search ADS PubMed WorldCat 33 Mazer CD , Hare GMT, Connelly PW, Gilbert RE, Shehata N, Quan A, Teoh H, Leiter LA, Zinman B, Jüni P, Zuo F, Mistry N, Thorpe KE, Goldenberg RM, Yan AT, Connelly KA, Verma S. Effect of empagliflozin on erythropoietin levels, iron stores and red blood cell morphology in patients with type 2 diabetes and coronary artery disease . Circulation 2019 ;doi:10.1161/circulationaha.119.044235. Google Scholar OpenURL Placeholder Text WorldCat 34 Murakami Y , Zhang Y, Cho YK, Mansoor AM, Chung JK, Chu C, Francis G, Ugurbil K, Bache RJ, From AH, Jerosch-Herold M, Wilke N, Zhang J. Myocardial oxygenation during high work states in hearts with postinfarction remodeling . Circulation 1999 ; 99 : 942 – 948 . Google Scholar Crossref Search ADS PubMed WorldCat 35 Swedberg K , Young JB, Anand IS, Cheng S, Desai AS, Diaz R, Maggioni AP, McMurray JJV, O’Connor C, Pfeffer MA, Solomon SD, Sun Y, Tendera M, van Veldhuisen DJ; RED-HF Committees, RED-HF Investigators. Treatment of anemia with darbepoetin alfa in systolic heart failure . N Engl J Med 2013 ; 368 : 1210 – 1219 . Google Scholar Crossref Search ADS PubMed WorldCat 36 Inzucchi SE , Zinman B, Fitchett D, Wanner C, Ferrannini E, Schumacher M, Schmoor C, Ohneberg K, Johansen OE, George JT, Hantel S, Bluhmki E, Lachin JM. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial . Diabetes Care 2018 ; 41 : 356 – 363 . Google Scholar Crossref Search ADS PubMed WorldCat 37 Li JW , Woodward M, Perkovic V, Figtree GA, Heerspink HJL, Mahaffey KW, de Zeeuw D, Vercruysse F, Shaw W, Matthews DR, Neal B. Mediators of the effects of canagliflozin on heart failure in patients with type 2 diabetes . JACC Heart Fail 2019 ;doi:10.1016/j.jchf.2019.08.004. Google Scholar OpenURL Placeholder Text WorldCat 38 Wang GL , Semenza GL. Purification and characterization of hypoxia-inducible factor 1 . J Biol Chem 1995 ; 270 : 1230 – 1237 . Google Scholar Crossref Search ADS PubMed WorldCat 39 Eckardt KU , Kurtz A. Regulation of erythropoietin production . Eur J Clin Invest 2005 ; 35 (Suppl. 3): 13 – 19 . Google Scholar Crossref Search ADS PubMed WorldCat 40 Papandreou I , Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption . Cell Metab 2006 ; 3 : 187 – 197 . Google Scholar Crossref Search ADS PubMed WorldCat 41 Zhdanov AV , Dmitriev RI, Golubeva AV, Gavrilova SA, Papkovsky DB. Chronic hypoxia leads to a glycolytic phenotype and suppressed HIF-2 signaling in PC12 cells . Biochim Biophys Acta 2013 ; 1830 : 3553 – 3569 . Google Scholar Crossref Search ADS PubMed WorldCat 42 Krishan P , Singh G, Bedi O. Carbohydrate restriction ameliorates nephropathy by reducing oxidative stress and upregulating HIF-1α levels in type-1 diabetic rats . J Diabetes Metab Disord 2017 ; 16 : 47 . Google Scholar Crossref Search ADS PubMed WorldCat 43 Ramakrishnan SK , Shah YM. A central role for hypoxia-inducible factor (HIF)-2α in hepatic glucose homeostasis . Nutr Healthy Aging 2017 ; 4 : 207 – 216 . Google Scholar Crossref Search ADS PubMed WorldCat 44 Zhdanov AV , Waters AH, Golubeva AV, Papkovsky DB. Differential contribution of key metabolic substrates and cellular oxygen in HIF signalling . Exp Cell Res 2015 ; 330 : 13 – 28 . Google Scholar Crossref Search ADS PubMed WorldCat 45 Brusselmans K , Bono F, Maxwell P, Dor Y, Dewerchin M, Collen D, Herbert JM, Carmeliet P. Hypoxia-inducible factor-2alpha (HIF-2alpha) is involved in the apoptotic response to hypoglycemia but not to hypoxia . J Biol Chem 2001 ; 276 : 39192 – 39196 . Google Scholar Crossref Search ADS PubMed WorldCat 46 Park SK , Dadak AM, Haase VH, Fontana L, Giaccia AJ, Johnson RS. Hypoxia-induced gene expression occurs solely through the action of hypoxia-inducible factor 1alpha (HIF-1alpha): role of cytoplasmic trapping of HIF-2alpha . Mol Cell Biol 2003 ; 23 : 4959 – 4971 . Google Scholar Crossref Search ADS PubMed WorldCat 47 Meng X , Tan J, Li M, Song S, Miao Y, Zhang Q. SIRT1: role under the condition of ischemia/hypoxia . Cell Mol Neurobiol 2017 ; 37 : 17 – 28 . Google Scholar Crossref Search ADS PubMed WorldCat 48 Li ZL , Lerman LO. Impaired myocardial autophagy linked to energy metabolism disorders . Autophagy 2012 ; 8 : 992 – 994 . Google Scholar Crossref Search ADS PubMed WorldCat 49 Rodgers JT , Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1 . Nature 2005 ; 434 : 113 – 118 . Google Scholar Crossref Search ADS PubMed WorldCat 50 Elibol B , Kilic U. High levels of SIRT1 expression as a protective mechanism against disease-related conditions . Front Endocrinol 2018 ; 9 : 614 . Google Scholar Crossref Search ADS WorldCat 51 Kane AE , Sinclair DA. Sirtuins and NAD+ in the development and treatment of metabolic and cardiovascular diseases . Circ Res 2018 ; 123 : 868 – 885 . Google Scholar Crossref Search ADS PubMed WorldCat 52 Kitada M , Kume S, Takeda-Watanabe A, Kanasaki K, Koya D. Sirtuins and renal diseases: relationship with aging and diabetic nephropathy . Clin Sci 2013 ; 124 : 153 – 164 . Google Scholar Crossref Search ADS WorldCat 53 Rubinsztein DC , Mariño G, Kroemer G. Autophagy and aging . Cell 2011 ; 146 : 682 – 695 . Google Scholar Crossref Search ADS PubMed WorldCat 54 Rankin EB , Rha J, Selak MA, Unger TL, Keith B, Liu Q, Haase VH. Hypoxia-inducible factor 2 regulates hepatic lipid metabolism . Mol Cell Biol 2009 ; 29 : 4527 – 4538 . Google Scholar Crossref Search ADS PubMed WorldCat 55 Qu A , Taylor M, Xue X, Matsubara T, Metzger D, Chambon P, Gonzalez FJ, Shah YM. Hypoxia-inducible transcription factor 2α promotes steatohepatitis through augmenting lipid accumulation, inflammation, and fibrosis . Hepatology 2011 ; 54 : 472 – 483 . Google Scholar Crossref Search ADS PubMed WorldCat 56 Liu Y , Ma Z, Zhao C, Wang Y, Wu G, Xiao J, McClain CJ, Li X, Feng W. HIF-1α and HIF-2α are critically involved in hypoxia-induced lipid accumulation in hepatocytes through reducing PGC-1α-mediated fatty acid β-oxidation . Toxicol Lett 2014 ; 226 : 117 – 123 . Google Scholar Crossref Search ADS PubMed WorldCat 57 Kucejova B , Sunny NE, Nguyen AD, Hallac R, Fu X, Peña-Llopis S, Mason RP, Deberardinis RJ, Xie XJ, Debose-Boyd R, Kodibagkar VD, Burgess SC, Brugarolas J. Uncoupling hypoxia signaling from oxygen sensing in the liver results in hypoketotic hypoglycemic death . Oncogene 2011 ; 30 : 2147 – 2160 . Google Scholar Crossref Search ADS PubMed WorldCat 58 Gillum MP , Erion DM, Shulman GI. Sirtuin-1 regulation of mammalian metabolism . Trends Mol Med 2011 ; 17 : 8 – 13 . Google Scholar Crossref Search ADS PubMed WorldCat 59 Hallows WC , Yu W, Denu JM. Regulation of glycolytic enzyme phosphoglycerate mutase-1 by SIRT1 protein-mediated deacetylation . J Biol Chem 2012 ; 287 : 3850 – 3858 . Google Scholar Crossref Search ADS PubMed WorldCat 60 Hirschey MD , Shimazu T, Capra JA, Pollard KS, Verdin E. SIRT1 and SIRT3 deacetylate homologous substrates: aceCS1,2 and HMGCS1,2 . Aging 2011 ; 3 : 635 – 642 . Google Scholar Crossref Search ADS PubMed WorldCat 61 Schönenberger MJ , Kovacs WJ. Hypoxia signaling pathways: modulators of oxygen-related organelles . Front Cell Dev Biol 2015 ; 3 : 42 . Google Scholar Crossref Search ADS PubMed WorldCat 62 Tang BL. SIRT1 and the mitochondria . Mol Cell 2016 ; 39 : 87 – 95 . Google Scholar Crossref Search ADS WorldCat 63 Planavila A , Iglesias R, Giralt M, Villarroya F. SIRT1 acts in association with PPARα to protect the heart from hypertrophy, metabolic dysregulation, and inflammation . Cardiovasc Res 2011 ; 90 : 276 – 284 . Google Scholar Crossref Search ADS PubMed WorldCat 64 Gano LB , Donato AJ, Pasha HM, Hearon CM Jr, Sindler AL, Seals DR. The SIRT1 activator SRT1720 reverses vascular endothelial dysfunction, excessive superoxide production, and inflammation with aging in mice . Am J Physiol Heart Circ Physiol 2014 ; 307 : H1754 – H1763 . Google Scholar Crossref Search ADS PubMed WorldCat 65 Wang T , Liu H, Lian G, Zhang SY, Wang X, Jiang C. HIF1α-induced glycolysis metabolism is essential to the activation of inflammatory macrophages . Mediators Inflamm 2017 ; 2017 : 1 – 10 . Google Scholar OpenURL Placeholder Text WorldCat 66 Tawakol A , Singh P, Mojena M, Pimentel-Santillana M, Emami H, MacNabb M, Rudd JH, Narula J, Enriquez JA, Través PG, Fernández-Velasco M, Bartrons R, Martín-Sanz P, Fayad ZA, Tejedor A, Boscá L. HIF-1α and PFKFB3 mediate a tight relationship between proinflammatory activation and anerobic metabolism in atherosclerotic macrophages . Arterioscler Thromb Vasc Biol 2015 ; 35 : 1463 – 1471 . Google Scholar Crossref Search ADS PubMed WorldCat 67 Charron CE , Chou PC, Coutts DJ, Kumar V, To M, Akashi K, Pinhu L, Griffiths M, Adcock IM, Barnes PJ, Ito K. Hypoxia-inducible factor 1alpha induces corticosteroid-insensitive inflammation via reduction of histone deacetylase-2 transcription . J Biol Chem 2009 ; 284 : 36047 – 36054 . Google Scholar Crossref Search ADS PubMed WorldCat 68 Fitzpatrick SF , Tambuwala MM, Bruning U, Schaible B, Scholz CC, Byrne A, O’Connor A, Gallagher WM, Lenihan CR, Garvey JF, Howell K, Fallon PG, Cummins EP, Taylor CT. An intact canonical NF-κB pathway is required for inflammatory gene expression in response to hypoxia . J Immunol 2011 ; 186 : 1091 – 1096 . Google Scholar Crossref Search ADS PubMed WorldCat 69 Bonello S , ZäHringer C, BelAiba RS, Djordjevic T, Hess J, Michiels C, Kietzmann T, GöRlach A. Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site . Arterioscler Thromb Vasc Biol 2007 ; 27 : 755 – 761 . Google Scholar Crossref Search ADS PubMed WorldCat 70 Choe SS , Shin KC, Ka S, Lee YK, Chun JS, Kim JB. Macrophage HIF-2α ameliorates adipose tissue inflammation and insulin resistance in obesity . Diabetes 2014 ; 63 : 3359 – 3371 . Google Scholar Crossref Search ADS PubMed WorldCat 71 Albrecht M , Zitta K, Bein B, Wennemuth G, Broch O, Renner J, Schuett T, Lauer F, Maahs D, Hummitzsch L, Cremer J, Zacharowski K, Meybohm P. Remote ischemic preconditioning regulates HIF-1α levels, apoptosis and inflammation in heart tissue of cardiosurgical patients: a pilot experimental study . Basic Res Cardiol 2013 ; 108 : 314 . Google Scholar Crossref Search ADS PubMed WorldCat 72 Wei Q , Bian Y, Yu F, Zhang Q, Zhang G, Li Y, Song S, Ren X, Tong J. Chronic intermittent hypoxia induces cardiac inflammation and dysfunction in a rat obstructive sleep apnea model . J Biomed Res 2016 ; 30 : 490 – 495 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 73 Bautista L , Castro MJ, López-Barneo J, Castellano A. Hypoxia inducible factor-2alpha stabilization and maxi-K+ channel beta1-subunit gene repression by hypoxia in cardiac myocytes: role in preconditioning . Circ Res 2009 ; 104 : 1364 – 1372 . Google Scholar Crossref Search ADS PubMed WorldCat 74 Mastrocola R , Collino M, Penna C, Nigro D, Chiazza F, Fracasso V, Tullio F, Alloatti G, Pagliaro P, Aragno M. Maladaptive modulations of NLRP3 inflammasome and cardioprotective pathways are involved in diet-induced exacerbation of myocardial ischemia/reperfusion injury in mice . Oxid Med Cell Longev 2016 ; 2016 : 1 – 12 . Google Scholar OpenURL Placeholder Text WorldCat 75 Bao W , Qin P, Needle S, Erickson-Miller CL, Duffy KJ, Ariazi JL, Zhao S, Olzinski AR, Behm DJ, Pipes GC, Jucker BM, Hu E, Lepore JJ, Willette RN. Chronic inhibition of hypoxia-inducible factor prolyl 4-hydroxylase improves ventricular performance, remodeling, and vascularity after myocardial infarction in the rat . J Cardiovasc Pharmacol 2010 ; 56 : 147 – 155 . Google Scholar Crossref Search ADS PubMed WorldCat 76 Natarajan R , Salloum FN, Fisher BJ, Ownby ED, Kukreja RC, Fowler AA III. Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium . Am J Physiol Heart Circ Physiol 2007 ; 293 : H1571 – H1580 . Google Scholar Crossref Search ADS PubMed WorldCat 77 Zeng H , Chen JX. Conditional knockout of prolyl hydroxylase domain protein 2 attenuates high fat-diet-induced cardiac dysfunction in mice . PLoS One 2014 ; 9 : e115974 . Google Scholar Crossref Search ADS PubMed WorldCat 78 Nwogu JI , Geenen D, Bean M, Brenner MC, Huang X, Buttrick PM. Inhibition of collagen synthesis with prolyl 4-hydroxylase inhibitor improves left ventricular function and alters the pattern of left ventricular dilatation after myocardial infarction . Circulation 2001 ; 104 : 2216 – 2221 . Google Scholar Crossref Search ADS PubMed WorldCat 79 Dioum EM , Chen R, Alexander MS, Zhang Q, Hogg RT, Gerard RD, Garcia JA. Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1 . Science 2009 ; 324 : 1289 – 1293 . Google Scholar Crossref Search ADS PubMed WorldCat 80 Chen R , Dioum EM, Hogg RT, Gerard RD, Garcia JA. Hypoxia increases sirtuin 1 expression in a hypoxia-inducible factor-dependent manner . J Biol Chem 2011 ; 286 : 13869 – 13878 . Google Scholar Crossref Search ADS PubMed WorldCat 81 Cui L , Guo J, Zhang Q, Yin J, Li J, Zhou W, Zhang T, Yuan H, Zhao J, Zhang L, Carmichael PL, Peng S. Erythropoietin activates SIRT1 to protect human cardiomyocytes against doxorubicin-induced mitochondrial dysfunction and toxicity . Toxicol Lett 2017 ; 275 : 28 – 38 . Google Scholar Crossref Search ADS PubMed WorldCat 82 Balaiya S , Khetpal V, Chalam KV. Hypoxia initiates sirtuin1-mediated vascular endothelial growth factor activation in choroidal endothelial cells through hypoxia inducible factor-2α . Mol Vis 2012 ; 18 : 114 – 120 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 83 Levine B , Packer M, Codogno P. Development of autophagy inducers in clinical medicine . J Clin Invest 2015 ; 125 : 14 – 24 . Google Scholar Crossref Search ADS PubMed WorldCat 84 Neary MT , Ng KE, Ludtmann MH, Hall AR, Piotrowska I, Ong SB, Hausenloy DJ, Mohun TJ, Abramov AY, Breckenridge RA. Hypoxia signaling controls postnatal changes in cardiac mitochondrial morphology and function . J Mol Cell Cardiol 2014 ; 74 : 340 – 352 . Google Scholar Crossref Search ADS PubMed WorldCat 85 Sciarretta S , Maejima Y, Zablocki D, Sadoshima J. The role of autophagy in the heart . Annu Rev Physiol 2018 ; 80 : 1 – 26 . Google Scholar Crossref Search ADS PubMed WorldCat 86 Kobayashi S , Liang Q. Autophagy and mitophagy in diabetic cardiomyopathy . Biochim Biophys Acta 2015 ; 1852 : 252 – 261 . Google Scholar Crossref Search ADS PubMed WorldCat 87 Shih H , Lee B, Lee RJ, Boyle AJ. The aging heart and post-infarction left ventricular remodeling . J Am Coll Cardiol 2011 ; 57 : 9 – 17 . Google Scholar Crossref Search ADS PubMed WorldCat 88 Bartlett JJ , Trivedi PC, Yeung P, Kienesberger PC, Pulinilkunnil T. Doxorubicin impairs cardiomyocyte viability by suppressing transcription factor EB expression and disrupting autophagy . Biochem J 2016 ; 473 : 3769 – 3789 . Google Scholar Crossref Search ADS PubMed WorldCat 89 Wang B , Nie J, Wu L, Hu Y, Wen Z, Dong L, Zou MH, Chen C, Wang DW. AMPKα2 protects against the development of heart failure by enhancing mitophagy via PINK1 phosphorylation . Circ Res 2018 ; 122 : 712 – 729 . Google Scholar Crossref Search ADS PubMed WorldCat 90 Bhuiyan MS , Pattison JS, Osinska H, James J, Gulick J, McLendon PM, Hill JA, Sadoshima J, Robbins J. Enhanced autophagy ameliorates cardiac proteinopathy . J Clin Invest 2013 ; 123 : 5284 – 5297 . Google Scholar Crossref Search ADS PubMed WorldCat 91 Xie Z , Lau K, Eby B, Lozano P, He C, Pennington B, Li H, Rathi S, Dong Y, Tian R, Kem D, Zou MH. Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice . Diabetes 2011 ; 60 : 1770 – 1778 . Google Scholar Crossref Search ADS PubMed WorldCat 92 Sala-Mercado JA , Wider J, Undyala VV, Jahania S, Yoo W, Mentzer RM Jr, Gottlieb RA, Przyklenk K. Profound cardioprotection with chloramphenicol succinate in the swine model of myocardial ischemia-reperfusion injury . Circulation 2010 ; 122 (11 Suppl): S179 –S1 84 . Google Scholar Crossref Search ADS PubMed WorldCat 93 Sciarretta S , Yee D, Nagarajan N, Bianchi F, Saito T, Valenti V, Tong M, Del Re DP, Vecchione C, Schirone L, Forte M, Rubattu S, Shirakabe A, Boppana VS, Volpe M, Frati G, Zhai P, Sadoshima J. Trehalose-induced activation of autophagy improves cardiac remodeling after myocardial infarction . J Am Coll Cardiol 2018 ; 71 : 1999 – 2010 . Google Scholar Crossref Search ADS PubMed WorldCat 94 Luo G , Jian Z, Zhu Y, Zhu Y, Chen B, Ma R, Tang F, Xiao Y. SIRT1 promotes autophagy and inhibits apoptosis to protect cardiomyocytes from hypoxic stress . Int J Mol Med 2019 ; 43 : 2033 – 2043 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 95 Qiu R , Li W, Liu Y. MicroRNA-204 protects H9C2 cells against hypoxia/reoxygenation-induced injury through regulating SIRT1-mediated autophagy . Biomed Pharmacother 2018 ; 100 : 15 – 19 . Google Scholar Crossref Search ADS PubMed WorldCat 96 Gyongyosi A , Terraneo L, Bianciardi P, Tosaki A, Lekli I, Samaja M. The impact of moderate chronic hypoxia and hyperoxia on the level of apoptotic and autophagic proteins in myocardial tissue . Oxid Med Cell Longev 2018 ; 2018 : 1 – 12 . Google Scholar Crossref Search ADS WorldCat 97 Zhang Y , Liu D, Hu H, Zhang P, Xie R, Cui W. HIF-1α/BNIP3 signaling pathway-induced-autophagy plays protective role during myocardial ischemia-reperfusion injury . Biomed Pharmacother 2019 ; 120 : 109464 . Google Scholar Crossref Search ADS PubMed WorldCat 98 Ren J , Yang L, Zhu L, Xu X, Ceylan AF, Guo W, Yang J, Zhang Y. Akt2 ablation prolongs life span and improves myocardial contractile function with adaptive cardiac remodeling: role of SIRT1-mediated autophagy regulation . Aging Cell 2017 ; 16 : 976 – 987 . Google Scholar Crossref Search ADS PubMed WorldCat 99 Gui L , Liu B, Lv G. Hypoxia induces autophagy in cardiomyocytes via a hypoxia-inducible factor 1-dependent mechanism . Exp Ther Med 2016 ; 11 : 2233 – 2239 . Google Scholar Crossref Search ADS PubMed WorldCat 100 Schönenberger MJ , Krek W, Kovacs WJ. EPAS1/HIF-2α is a driver of mammalian pexophagy . Autophagy 2015 ; 11 : 967 – 969 . Google Scholar Crossref Search ADS PubMed WorldCat 101 Walter KM , Schönenberger MJ, Trötzmüller M, Horn M, Elsässer HP, Moser AB, Lucas MS, Schwarz T, Gerber PA, Faust PL, Moch H, Köfeler HC, Krek W, Kovacs WJ. HIF-2α promotes degradation of mammalian peroxisomes by selective autophagy . Cell Metab 2014 ; 20 : 882 – 897 . Google Scholar Crossref Search ADS PubMed WorldCat 102 Ong SG , Lee WH, Theodorou L, Kodo K, Lim SY, Shukla DH, Briston T, Kiriakidis S, Ashcroft M, Davidson SM, Maxwell PH, Yellon DM, Hausenloy DJ. HIF-1 reduces ischaemia-reperfusion injury in the heart by targeting the mitochondrial permeability transition pore . Cardiovasc Res 2014 ; 104 : 24 – 36 . Google Scholar Crossref Search ADS PubMed WorldCat 103 Cerychova R , Pavlinkova G. HIF-1, metabolism, and diabetes in the embryonic and adult heart . Front Endocrinol 2018 ; 9 : 460 . Google Scholar Crossref Search ADS WorldCat 104 Nanayakkara G , Alasmari A, Mouli S, Eldoumani H, Quindry J, McGinnis G, Fu X, Berlin A, Peters B, Zhong J, Amin R. Cardioprotective HIF-1α-frataxin signaling against ischemia-reperfusion injury . Am J Physiol Heart Circ Physiol 2015 ; 309 : H867 –H8 79 . Google Scholar Crossref Search ADS PubMed WorldCat 105 Neckář J , Hsu A, Hye Khan MA, Gross GJ, Nithipatikom K, Cyprová M, Benák D, Hlaváčková M, Sotáková-Kašparová D, Falck JR, Sedmera D, Kolář F, Imig JD. Infarct size-limiting effect of epoxyeicosatrienoic acid analog EET-B is mediated by hypoxia-inducible factor-1α via downregulation of prolyl hydroxylase 3 . Am J Physiol Heart Circ Physiol 2018 ; 315 : H1148 – H1158 . Google Scholar Crossref Search ADS PubMed WorldCat 106 Koeppen M , Lee JW, Seo SW, Brodsky KS, Kreth S, Yang IV, Buttrick PM, Eckle T, Eltzschig HK. Hypoxia-inducible factor 2-alpha-dependent induction of amphiregulin dampens myocardial ischemia-reperfusion injury . Nat Commun 2018 ; 9 : 816 . Google Scholar Crossref Search ADS PubMed WorldCat 107 Hyvärinen J , Hassinen IE, Sormunen R, Mäki JM, Kivirikko KI, Koivunen P, Myllyharju J. Hearts of hypoxia-inducible factor prolyl 4-hydroxylase-2 hypomorphic mice show protection against acute ischemia-reperfusion injury . J Biol Chem 2010 ; 285 : 13646 – 13657 . Google Scholar Crossref Search ADS PubMed WorldCat 108 Wei H , Bedja D, Koitabashi N, Xing D, Chen J, Fox-Talbot K, Rouf R, Chen S, Steenbergen C, Harmon JW, Dietz HC, Gabrielson KL, Kass DA, Semenza GL. Endothelial expression of hypoxia-inducible factor 1 protects the murine heart and aorta from pressure overload by suppression of TGF-β signaling . Proc Natl Acad Sci U S A 2012 ; 109 : E841 –E8 50 . Google Scholar Crossref Search ADS PubMed WorldCat 109 Krishnan J , Suter M, Windak R, Krebs T, Felley A, Montessuit C, Tokarska-Schlattner M, Aasum E, Bogdanova A, Perriard E, Perriard JC, Larsen T, Pedrazzini T, Krek W. Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy . Cell Metab 2009 ; 9 : 512 – 524 . Google Scholar Crossref Search ADS PubMed WorldCat 110 Hölscher M , Schäfer K, Krull S, Farhat K, Hesse A, Silter M, Lin Y, Pichler BJ, Thistlethwaite P, El-Armouche A, Maier LS, Katschinski DM, Zieseniss A. Unfavourable consequences of chronic cardiac HIF-1α stabilization . Cardiovasc Res 2012 ; 94 : 77 – 86 . Google Scholar Crossref Search ADS PubMed WorldCat 111 Bekeredjian R , Walton CB, MacCannell KA, Ecker J, Kruse F, Outten JT, Sutcliffe D, Gerard RD, Bruick RK, Shohet RV, Bruick RK. Conditional HIF-1alpha expression produces a reversible cardiomyopathy . PLoS One 2010 ; 5 : e11693 . Google Scholar Crossref Search ADS PubMed WorldCat 112 Liu X , Gao Y, Li M, Geng C, Xu H, Yang Y, Guo Y, Jiao T, Fang F, Chang Y. SIRT1 mediates the effect of the heme oxygenase inducer, cobalt protoporphyrin, on ameliorating liver metabolic damage caused by a high-fat diet . J Hepatol 2015 ; 63 : 713 – 721 . Google Scholar Crossref Search ADS PubMed WorldCat 113 Rane S , He M, Sayed D, Vashistha H, Malhotra A, Sadoshima J, Vatner DE, Vatner SF, Abdellatif M. Downregulation of miR-199a derepresses hypoxia-inducible factor-1alpha and sirtuin 1 and recapitulates hypoxia preconditioning in cardiac myocytes . Circ Res 2009 ; 104 : 879 – 886 . Google Scholar Crossref Search ADS PubMed WorldCat 114 Joo HY , Yun M, Jeong J, Park ER, Shin HJ, Woo SR, Jung JK, Kim YM, Park JJ, Kim J, Lee KH. SIRT1 deacetylates and stabilizes hypoxia-inducible factor-1α (HIF-1α) via direct interactions during hypoxia . Biochem Biophys Res Commun 2015 ; 462 : 294 – 300 . Google Scholar Crossref Search ADS PubMed WorldCat 115 Laemmle A , Lechleiter A, Roh V, Schwarz C, Portmann S, Furer C, Keogh A, Tschan MP, Candinas D, Vorburger SA, Stroka D. Inhibition of SIRT1 impairs the accumulation and transcriptional activity of HIF-1α protein under hypoxic conditions . PLoS One 2012 ; 7 : e33433 . Google Scholar Crossref Search ADS PubMed WorldCat 116 Ryu DR , Yu MR, Kong KH, Kim H, Kwon SH, Jeon JS, Han DC, Noh H. SIRT1-hypoxia-inducible factor-1α interaction is a key mediator of tubulointerstitial damage in the aged kidney . Aging Cell 2019 ; 18 : e12904 . Google Scholar Crossref Search ADS PubMed WorldCat 117 Lim JH , Lee YM, Chun YS, Chen J, Kim JE, Park JW. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha . Mol Cell 2010 ; 38 : 864 – 878 . Google Scholar Crossref Search ADS PubMed WorldCat 118 Wang S , Qian Y, Gong D, Zhang Y, Fan Y. Resveratrol attenuates acute hypoxic injury in cardiomyocytes: correlation with inhibition of iNOS-NO signaling pathway . Eur J Pharm Sci 2011 ; 44 : 416 – 421 . Google Scholar Crossref Search ADS PubMed WorldCat 119 Tao A , Xu X, Kvietys P, Kao R, Martin C, Rui T. Experimental diabetes mellitus exacerbates ischemia/reperfusion-induced myocardial injury by promoting mitochondrial fission: role of down-regulation of myocardial SIRT1 and subsequent Akt/Drp1 interaction . Int J Biochem Cell Biol 2018 ; 105 : 94 – 103 . Google Scholar Crossref Search ADS PubMed WorldCat 120 Sanz MN , Grimbert L, Moulin M, Gressette M, Rucker-Martin C, Lemaire C, Mericskay M, Veksler V, Ventura-Clapier R, Garnier A, Piquereau J. Inducible cardiac-specific deletion of SIRT1 in male mice reveals progressive cardiac dysfunction and sensitization of the heart to pressure overload . Int J Mol Sci 2019 ; 20 :E5005. Google Scholar OpenURL Placeholder Text WorldCat 121 Tada Y , Ogawa M, Watanabe R, Zempo H, Takamura C, Suzuki J, Dan T, Miyata T, Isobe M, Komuro I. Neovascularization induced by hypoxia inducible transcription factor is associated with the improvement of cardiac dysfunction in experimental autoimmune myocarditis . Expert Opin Invest Drugs 2014 ; 23 : 149 – 162 . Google Scholar Crossref Search ADS WorldCat 122 Yuan YP , Ma ZG, Zhang X, Xu SC, Zeng XF, Yang Z, Deng W, Tang QZ. CTRP3 protected against doxorubicin-induced cardiac dysfunction, inflammation and cell death via activation of SIRT1 . J Mol Cell Cardiol 2018 ; 114 : 38 – 47 . Google Scholar Crossref Search ADS PubMed WorldCat 123 Wang L , Quan N, Sun W, Chen X, Cates C, Rousselle T, Zhou X, Zhao X, Li J. Cardiomyocyte-specific deletion of SIRT1 gene sensitizes myocardium to ischaemia and reperfusion injury . Cardiovasc Res 2018 ; 114 : 805 – 821 . Google Scholar Crossref Search ADS PubMed WorldCat 124 Spagnuolo RD , Recalcati S, Tacchini L, Cairo G. Role of hypoxia-inducible factors in the dexrazoxane-mediated protection of cardiomyocytes from doxorubicin-induced toxicity . Br J Pharmacol 2011 ; 163 : 299 – 312 . Google Scholar Crossref Search ADS PubMed WorldCat 125 Zapata-Morales JR , Galicia-Cruz OG, Franco M, Martinez Y Morales F. Hypoxia-inducible factor-1α (HIF-1α) protein diminishes sodium glucose transport 1 (SGLT1) and SGLT2 protein expression in renal epithelial tubular cells (LLC-PK1) under hypoxia . J Biol Chem 2014 ; 289 : 346 – 357 . Google Scholar Crossref Search ADS PubMed WorldCat 126 Umino H , Hasegawa K, Minakuchi H, Muraoka H, Kawaguchi T, Kanda T, Tokuyama H, Wakino S, Itoh H. High basolateral glucose increases sodium-glucose cotransporter 2 and reduces sirtuin-1 in renal tubules through glucose transporter-2 detection . Sci Rep 2018 ; 8 : 6791 . Google Scholar Crossref Search ADS PubMed WorldCat 127 Sasaki M , Sasako T, Kubota N, Sakurai Y, Takamoto I, Kubota T, Inagi R, Seki G, Goto M, Ueki K, Nangaku M, Jomori T, Kadowaki T. Dual regulation of gluconeogenesis by insulin and glucose in the proximal tubules of the kidney . Diabetes 2017 ; 66 : 2339 – 2350 . Google Scholar Crossref Search ADS PubMed WorldCat 128 Kim JW , Lee YJ, You YH, Moon MK, Yoon KH, Ahn YB, Ko SH. Effect of sodium-glucose cotransporter 2 inhibitor, empagliflozin, and α-glucosidase inhibitor, voglibose, on hepatic steatosis in an animal model of type 2 diabetes . J Cell Biochem 2018 ;doi:10.1002/jcb.28141. Google Scholar OpenURL Placeholder Text WorldCat 129 Ying Y , Jiang C, Zhang M, Jin J, Ge S, Wang X. Phloretin protects against cardiac damage and remodeling via restoring SIRT1 and anti-inflammatory effects in the streptozotocin-induced diabetic mouse model . Aging 2019 ; 11 : 2822 – 2835 . Google Scholar Crossref Search ADS PubMed WorldCat 130 Paliege A , Rosenberger C, Bondke A, Sciesielski L, Shina A, Heyman SN, Flippin LA, Arend M, Klaus SJ, Bachmann S. Hypoxia-inducible factor-2alpha-expressing interstitial fibroblasts are the only renal cells that express erythropoietin under hypoxia-inducible factor stabilization . Kidney Int 2010 ; 77 : 312 – 318 . Google Scholar Crossref Search ADS PubMed WorldCat 131 Kurt B , Gerl K, Karger C, Schwarzensteiner I, Kurtz A. Chronic hypoxia-inducible transcription factor-2 activation stably transforms juxtaglomerular renin cells into fibroblast-like cells in vivo . J Am Soc Nephrol 2015 ; 26 : 587 – 596 . Google Scholar Crossref Search ADS PubMed WorldCat 132 Kapitsinou PP , Liu Q, Unger TL, Rha J, Davidoff O, Keith B, Epstein JA, Moores SL, Erickson-Miller CL, Haase VH. Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia . Blood 2010 ; 116 : 3039 – 3048 . Google Scholar Crossref Search ADS PubMed WorldCat 133 O’Neill J , Fasching A, Pihl L, Patinha D, Franzén S, Palm F. Acute SGLT inhibition normalizes O2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats . Am J Physiol Renal Physiol 2015 ; 309 : F227 –F2 34 . Google Scholar Crossref Search ADS PubMed WorldCat 134 Takiyama Y , Sera T, Nakamura M, Ishizeki K, Saijo Y, Yanagimachi T, Maeda M, Bessho R, Takiyama T, Kitsunai H, Sakagami H, Fujishiro D, Fujita Y, Makino Y, Abiko A, Hoshino M, Uesugi K, Yagi N, Ota T, Haneda M. Impacts of diabetes and an SGLT2 inhibitor on the glomerular number and volume in db/db mice, as estimated by synchrotron radiation micro-CT at SPring-8 . EBioMedicine 2018 ; 36 : 329 – 346 . Google Scholar Crossref Search ADS PubMed WorldCat 135 Chang YK , Choi H, Jeong JY, Na KR, Lee KW, Lim BJ, Choi DE. Dapagliflozin, SGLT2 inhibitor, attenuates renal ischemia-reperfusion injury . PLoS One 2016 ; 11 : e0158810 . Google Scholar Crossref Search ADS PubMed WorldCat 136 Bessho R , Takiyama Y, Takiyama T, Kitsunai H, Takeda Y, Sakagami H, Ota T. Hypoxia-inducible factor-1α is the therapeutic target of the SGLT2 inhibitor for diabetic nephropathy . Sci Rep 2019 ; 9 : 14754 . Google Scholar Crossref Search ADS PubMed WorldCat 137 Daniele G , Xiong J, Solis-Herrera C, Merovci A, Eldor R, Tripathy D, DeFronzo RA, Norton L, Abdul-Ghani M. Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes . Diabetes Care 2016 ; 39 : 2036 – 2041 . Google Scholar Crossref Search ADS PubMed WorldCat 138 Ferrannini E , Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, Broedl UC, Woerle HJ. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients . J Clin Invest 2014 ; 124 : 499 – 508 . Google Scholar Crossref Search ADS PubMed WorldCat 139 Xu L , Nagata N, Nagashimada M, Zhuge F, Ni Y, Chen G, Mayoux E, Kaneko S, Ota T. SGLT2 inhibition by empagliflozin promotes fat utilization and browning and attenuates inflammation and insulin resistance by polarizing M2 macrophages in diet-induced obese mice . EBioMedicine 2017 ; 20 : 137 – 149 . Google Scholar Crossref Search ADS PubMed WorldCat 140 Lee TM , Chang NC, Lin SZ. Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts . Free Radic Biol Med 2017 ; 104 : 298 – 310 . Google Scholar Crossref Search ADS PubMed WorldCat 141 Ye Y , Bajaj M, Yang HC, Perez-Polo JR, Birnbaum Y. SGLT-2 inhibition with dapagliflozin reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic cardiomyopathy in mice with type 2 diabetes. Further augmentation of the effects with saxagliptin, a DPP4 inhibitor . Cardiovasc Drugs Ther 2017 ; 31 : 119 – 132 . Google Scholar Crossref Search ADS PubMed WorldCat 142 Kumanto M , Paukkeri EL, Nieminen R, Moilanen E. Cobalt(II) chloride modifies the phenotype of macrophage activation . Basic Clin Pharmacol Toxicol 2017 ; 121 : 98 – 105 . Google Scholar Crossref Search ADS PubMed WorldCat 143 Osataphan S , Macchi C, Singhal G, Chimene-Weiss J, Sales V, Kozuka C, Dreyfuss JM, Pan H, Tangcharoenpaisan Y, Morningstar J, Gerszten R, Patti ME. SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms . JCI Insight 2019 ; 4 : 123130 . Google Scholar Crossref Search ADS PubMed WorldCat 144 Kim J , Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 . Nat Cell Biol 2011 ; 13 : 132 – 141 . Google Scholar Crossref Search ADS PubMed WorldCat 145 Aragón-Herrera A , Feijóo-Bandín S, Otero Santiago M, Barral L, Campos-Toimil M, Gil-Longo J, Costa Pereira TM, García-Caballero T, Rodríguez-Segade S, Rodríguez J, Tarazón E, Roselló-Lletí E, Portolés M, Gualillo O, González-Juanatey JR, Lago F. Empagliflozin reduces the levels of CD36 and cardiotoxic lipids while improving autophagy in the hearts of Zucker diabetic fatty rats . Biochem Pharmacol 2019 ; 170 : 113677 . Google Scholar Crossref Search ADS PubMed WorldCat 146 Hawley SA , Ford RJ, Smith BK, Gowans GJ, Mancini SJ, Pitt RD, Day EA, Salt IP, Steinberg GR, Hardie DG. The Na+/glucose cotransporter inhibitor canagliflozin activates AMPK by inhibiting mitochondrial function and increasing cellular AMP levels . Diabetes 2016 ; 65 : 2784 – 2794 . Google Scholar Crossref Search ADS PubMed WorldCat 147 Mancini SJ , Boyd D, Katwan OJ, Strembitska A, Almabrouk TA, Kennedy S, Palmer TM, Salt IP. Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms . Sci Rep 2018 ; 8 : 5276 . Google Scholar Crossref Search ADS PubMed WorldCat 148 Ye Y , Jia X, Bajaj M, Birnbaum Y. Dapagliflozin attenuates Na+/H+ exchanger-1 in cardiofibroblasts via AMPK activation . Cardiovasc Drugs Ther 2018 ; 32 : 553 – 558 . Google Scholar Crossref Search ADS PubMed WorldCat 149 Zhang H , Liu B, Li T, Zhu Y, Luo G, Jiang Y, Tang F, Jian Z, Xiao Y. AMPK activation serves a critical role in mitochondria quality control via modulating mitophagy in the heart under chronic hypoxia . Int J Mol Med 2018 ; 41 : 69 – 76 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 150 Maeda H , Nagai H, Takemura G, Shintani-Ishida K, Komatsu M, Ogura S, Aki T, Shirai M, Kuwahira I, Yoshida K. Intermittent-hypoxia induced autophagy attenuates contractile dysfunction and myocardial injury in rat heart . Biochim Biophys Acta 2013 ; 1832 : 1159 – 1166 . Google Scholar Crossref Search ADS PubMed WorldCat 151 Chen R , Jiang T, She Y, Xu J, Li C, Zhou S, Shen H, Shi H, Liu S. Effects of cobalt chloride, a hypoxia-mimetic agent, on autophagy and atrophy in skeletal C2C12 myotubes . Biomed Res Int 2017 ; 2017 : 7097580 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 152 Cantó C , Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity . Nature 2009 ; 458 : 1056 – 1060 . Google Scholar Crossref Search ADS PubMed WorldCat 153 Li H , Satriano J, Thomas JL, Miyamoto S, Sharma K, Pastor-Soler NM, Hallows KR, Singh P. Interactions between HIF-1α and AMPK in the regulation of cellular hypoxia adaptation in chronic kidney disease . Am J Physiol Renal Physiol 2015 ; 309 : F414 –F4 28 . Google Scholar Crossref Search ADS PubMed WorldCat 154 Bijland S , Mancini SJ, Salt IP. Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation . Clin Sci 2013 ; 124 : 491 – 507 . Google Scholar Crossref Search ADS WorldCat 155 Ladli M , Richard C, Aguilar LC, Ducamp S, Bondu S, Sujobert P, Tamburini J, Lacombe C, Azar N, Foretz M, Zermati Y, Mayeux P, Viollet B, Verdier F. Finely-tuned regulation of AMP-activated protein kinase is crucial for human adult erythropoiesis . Haematologica 2019 ; 104 : 907 – 918 . Google Scholar Crossref Search ADS PubMed WorldCat 156 Treins C , Murdaca J, Van Obberghen E, Giorgetti-Peraldi S. AMPK activation inhibits the expression of HIF-1alpha induced by insulin and IGF-1 . Biochem Biophys Res Commun 2006 ; 342 : 1197 – 1202 . Google Scholar Crossref Search ADS PubMed WorldCat 157 Ghezzi C , Yu AS, Hirayama BA, Kepe V, Liu J, Scafoglio C, Powell DR, Huang SC, Satyamurthy N, Barrio JR, Wright EM. Dapagliflozin binds specifically to sodium-glucose cotransporter 2 in the proximal renal tubule . J Am Soc Nephrol 2017 ; 28 : 802 – 810 . Google Scholar Crossref Search ADS PubMed WorldCat 158 Adingupu DD , Göpel SO, Grönros J, Behrendt M, Sotak M, Miliotis T, Dahlqvist U, Gan L-M, Jönsson-Rylander A-C. SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob-/- mice . Cardiovasc Diabetol 2019 ; 18 : 16 . Google Scholar Crossref Search ADS PubMed WorldCat 159 Takasu T , Takakura S. Effect of ipragliflozin, an SGLT2 inhibitor, on cardiac histopathological changes in a non-diabetic rat model of cardiomyopathy . Life Sci 2019 ; 230 : 19 – 27 . Google Scholar Crossref Search ADS PubMed WorldCat 160 Díaz-Rodríguez E , Agra RM, Fernández ÁL, Adrio B, García-Caballero T, González-Juanatey JR, Eiras S. Effects of dapagliflozin on human epicardial adipose tissue: modulation of insulin resistance, inflammatory chemokine production, and differentiation ability . Cardiovasc Res 2018 ; 114 : 336 – 346 . Google Scholar Crossref Search ADS PubMed WorldCat 161 Nambu H , Takada S, Fukushima A, Matsumoto J, Kakutani N, Maekawa S, Shirakawa R, Nakano I, Furihata T, Katayama T, Yamanashi K, Obata Y, Saito A, Yokota T, Kinugawa S. Empagliflozin restores lowered exercise endurance capacity via the activation of skeletal muscle fatty acid oxidation in a murine model of heart failure . Eur J Pharmacol 2020 ; 866 : 172810 . Google Scholar Crossref Search ADS PubMed WorldCat 162 Mizuno M , Kuno A, Yano T, Miki T, Oshima H, Sato T, Nakata K, Kimura Y, Tanno M, Miura T. Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts . Physiol Rep 2018 ; 6 : e13741 . Google Scholar Crossref Search ADS PubMed WorldCat 163 Xu C , Wang W, Zhong J, Lei F, Xu N, Zhang Y, Xie W. Canagliflozin exerts anti-inflammatory effects by inhibiting intracellular glucose metabolism and promoting autophagy in immune cells . Biochem Pharmacol 2018 ; 152 : 45 – 59 . Google Scholar Crossref Search ADS PubMed WorldCat 164 Lee YH , Kim SH, Kang JM, Heo JH, Kim DJ, Park SH, Sung M, Kim J, Oh J, Yang DH, Lee SH, Lee SY. Empagliflozin attenuates diabetic tubulopathy by improving mitochondrial fragmentation and autophagy . Am J Physiol Renal Physiol 2019 ; 317 : F767 – F780 . Google Scholar Crossref Search ADS PubMed WorldCat 165 Li C , Zhang J, Xue M, Li X, Han F, Liu X, Xu L, Lu Y, Cheng Y, Li T, Yu X, Sun B, Chen L. SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart . Cardiovasc Diabetol 2019 ; 18 : 15 . Google Scholar Crossref Search ADS PubMed WorldCat 166 Sayour AA , Korkmaz-Icöz S, Loganathan S, Ruppert M, Sayour VN, Oláh A, Benke K, Brune M, Benkő R, Horváth EM, Karck M, Merkely B, Radovits T, Szabó G. Acute canagliflozin treatment protects against in vivo myocardial ischemia-reperfusion injury in non-diabetic male rats and enhances endothelium-dependent vasorelaxation . J Transl Med 2019 ; 17 : 127 . Google Scholar Crossref Search ADS PubMed WorldCat 167 Packer M , Anker SD, Butler J, Filippatos G, Zannad F. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action . JAMA Cardiol 2017 ; 2 : 1025 – 1029 . Google Scholar Crossref Search ADS PubMed WorldCat 168 Bertero E , Prates Roma L, Ameri P, Maack C. Cardiac effects of SGLT2 inhibitors: the sodium hypothesis . Cardiovasc Res 2018 ; 114 : 12 – 18 . Google Scholar Crossref Search ADS PubMed WorldCat 169 Uthman L , Baartscheer A, Bleijlevens B, Schumacher CA, Fiolet JWT, Koeman A, Jancev M, Hollmann MW, Weber NC, Coronel R, Zuurbier CJ. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation . Diabetologia 2018 ; 61 : 722 – 726 . Google Scholar Crossref Search ADS PubMed WorldCat 170 Zhang D , Li S, Cruz P, Kone BC. Sirtuin 1 functionally and physically interacts with disruptor of telomeric silencing-1 to regulate alpha-ENaC transcription in collecting duct . J Biol Chem 2009 ; 284 : 20917 – 20926 . Google Scholar Crossref Search ADS PubMed WorldCat 171 Sowers JR , Habibi J, Aroor AR, Yang Y, Lastra G, Hill MA, Whaley-Connell A, Jaisser F, Jia G. Epithelial sodium channels in endothelial cells mediate diet-induced endothelium stiffness and impaired vascular relaxation in obese female mice . Metabolism 2019 ; 99 : 57 – 66 . Google Scholar Crossref Search ADS PubMed WorldCat 172 Wang P , Li L, Zhang Z, Kan Q, Gao F, Chen S. Time-dependent activity of Na+/H+ exchanger isoform 1 and homeostasis of intracellular pH in astrocytes exposed to CoCl2 treatment . Mol Med Rep 2016 ; 13 : 4443 – 4450 . Google Scholar Crossref Search ADS PubMed WorldCat 173 Yang J , Zhao X, Patel A, Potru R, Azizi-Ghannad S, Dolinger M, Cao J, Bartholomew C, Mazurkiewicz J, Conti D, Jones D, Huang Y, Zhu XC. Rapamycin inhibition of mTOR reduces levels of the Na+/H+ exchanger 3 in intestines of mice and humans, leading to diarrhea . Gastroenterology 2015 ; 149 : 151 – 162 . Google Scholar Crossref Search ADS PubMed WorldCat 174 Kanamori H , Takemura G, Goto K, Tsujimoto A, Mikami A, Ogino A, Watanabe T, Morishita K, Okada H, Kawasaki M, Seishima M, Minatoguchi S. Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes . Autophagy 2015 ; 11 : 1146 – 1160 . Google Scholar Crossref Search ADS PubMed WorldCat 175 Krzysiak TC , Thomas L, Choi YJ, Auclair S, Qian Y, Luan S, Krasnow SM, Thomas LL, Koharudin LMI, Benos PV, Marks DL, Gronenborn AM, Thomas G. An insulin-responsive sensor in the SIRT1 disordered region binds DBC1 and PACS-2 to control enzyme activity . Mol Cell 2018 ; 72 : 985 – 998.e7 . Google Scholar Crossref Search ADS PubMed WorldCat 176 Paula-Gomes S , Gonçalves DA, Baviera AM, Zanon NM, Navegantes LC, Kettelhut IC. Insulin suppresses atrophy- and autophagy-related genes in heart tissue and cardiomyocytes through AKT/FOXO signaling . Horm Metab Res 2013 ; 45 : 849 – 855 . Google Scholar Crossref Search ADS PubMed WorldCat 177 Zhang Y , Ling Y, Yang L, Cheng Y, Yang P, Song X, Tang H, Zhong Y, Tang L, He S, Yang S, Chen A, Wang X. Liraglutide relieves myocardial damage by promoting autophagy via AMPK-mTOR signaling pathway in Zucker diabetic fatty rat . Mol Cell Endocrinol 2017 ; 448 : 98 – 107 . Google Scholar Crossref Search ADS PubMed WorldCat 178 Qiao H , Ren H, Du H, Zhang M, Xiong X, Lv R. Liraglutide repairs the infarcted heart: the role of the SIRT1/Parkin/mitophagy pathway . Mol Med Rep 2018 ; 17 : 3722 – 3734 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 179 Kihira Y , Burentogtokh A, Itoh M, Izawa-Ishizawa Y, Ishizawa K, Ikeda Y, Tsuchiya K, Tamaki T. Hypoxia decreases glucagon-like peptide-1 secretion from the GLUTag cell line . Biol Pharm Bull 2015 ; 38 : 514 – 521 . Google Scholar Crossref Search ADS PubMed WorldCat 180 Kihira Y , Miyake M, Hirata M, Hoshina Y, Kato K, Shirakawa H, Sakaue H, Yamano N, Izawa-Ishizawa Y, Ishizawa K, Ikeda Y, Tsuchiya K, Tamaki T, Tomita S. Deletion of hypoxia-inducible factor-1α in adipocytes enhances glucagon-like peptide-1 secretion and reduces adipose tissue inflammation . PLoS One 2014 ; 9 : e93856 . Google Scholar Crossref Search ADS PubMed WorldCat 181 Zhou Y , Wang H, Man F, Guo Z, Xu J, Yan W, Li J, Pan Q, Wang W. Sitagliptin protects cardiac function by reducing nitroxidative stress and promoting autophagy in Zucker diabetic fatty (ZDF) rats . Cardiovasc Drugs Ther 2018 ; 32 : 541 – 552 . Google Scholar Crossref Search ADS PubMed WorldCat 182 Packer M. Have dipeptidyl peptidase-4 inhibitors ameliorated the vascular complications of type 2 diabetes in large-scale trials? The potential confounding effect of stem-cell chemokines . Cardiovasc Diabetol 2018 ; 17 : 9 . Google Scholar Crossref Search ADS PubMed WorldCat 183 Coly PM , Gandolfo P, Castel H, Morin F. The autophagy machinery: a new player in chemotactic cell migration . Front Neurosci 2017 ; 11 : 78 . Google Scholar Crossref Search ADS PubMed WorldCat 184 Kato MF , Shibata R, Obata K, Miyachi M, Yazawa H, Tsuboi K, Yamada T, Nishizawa T, Noda A, Cheng XW, Murate T, Koike Y, Murohara T, Yokota M, Nagata K. Pioglitazone attenuates cardiac hypertrophy in rats with salt-sensitive hypertension: role of activation of AMP-activ-ated protein kinase and inhibition of Akt . J Hypertens 2008 ; 26 : 1669 – 1676 . Google Scholar Crossref Search ADS PubMed WorldCat 185 Chraïbi A , Renauld S. PPARγ-induced stimulation of amiloride-sensitive sodium current in renal collecting duct principal cells is serum and insulin dependent . Cell Physiol Biochem 2014 ; 33 : 581 – 593 . Google Scholar Crossref Search ADS PubMed WorldCat 186 Zhou G , Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action . J Clin Invest 2001 ; 108 : 1167 – 1174 . Google Scholar Crossref Search ADS PubMed WorldCat 187 Gundewar S , Calvert JW, Jha S, Toedt-Pingel I, Ji SY, Nunez D, Ramachandran A, Anaya-Cisneros M, Tian R, Lefer DJ. Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure . Circ Res 2009 ; 104 : 403 – 411 . Google Scholar Crossref Search ADS PubMed WorldCat 188 Fulgencio JP , Kohl C, Girard J, Pégorier JP. Effect of metformin on fatty acid and glucose metabolism in freshly isolated hepatocytes and on specific gene expression in cultured hepatocytes . Biochem Pharmacol 2001 ; 62 : 439 – 446 . Google Scholar Crossref Search ADS PubMed WorldCat 189 Potthoff MJ , Inagaki T, Satapati S, Ding X, He T, Goetz R, Mohammadi M, Finck BN, Mangelsdorf DJ, Kliewer SA, Burgess SC. FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response . Proc Natl Acad Sci U S A 2009 ; 106 : 10853 – 10858 . Google Scholar Crossref Search ADS PubMed WorldCat 190 Diabetes Prevention Program Research Group. Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study . Diabetes Care 2012 ; 35 : 731 – 737 . Crossref Search ADS PubMed WorldCat 191 Li X , Li J, Wang L, Li A, Qiu Z, Qi LW, Kou J, Liu K, Liu B, Huang F. The role of metformin and resveratrol in the prevention of hypoxia-inducible factor 1α accumulation and fibrosis in hypoxic adipose tissue . Br J Pharmacol 2016 ; 173 : 2001 – 2015 . Google Scholar Crossref Search ADS PubMed WorldCat 192 Packer M. Is metformin beneficial for heart failure in patients with type 2 diabetes? Diabetes Res Clin Pract 2018 ; 136 : 168 – 170 . Google Scholar Crossref Search ADS PubMed WorldCat 193 Rådholm K , Figtree G, Perkovic V, Solomon SD, Mahaffey KW, de Zeeuw D, Fulcher G, Barrett TD, Shaw W, Desai M, Matthews DR, Neal B. Canagliflozin and heart failure in type 2 diabetes mellitus . Circulation 2018 ; 138 : 458 – 468 . Google Scholar Crossref Search ADS PubMed WorldCat 194 Fitchett D , Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Trial Investigators. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME trial . Eur Heart J 2016 ; 37 : 1526 – 1534 . Google Scholar Crossref Search ADS PubMed WorldCat Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Critical examination of mechanisms underlying the reduction in heart failure events with SGLT2 inhibitors: identification of a molecular link between their actions to stimulate erythrocytosis and to alleviate cellular stress
JF - Cardiovascular Research
DO - 10.1093/cvr/cvaa064
DA - 2021-01-01
UR - https://www.deepdyve.com/lp/oxford-university-press/critical-examination-of-mechanisms-underlying-the-reduction-in-heart-atIfcmsby9
SP - 74
EP - 84
VL - 117
IS - 1
DP - DeepDyve
ER -