Cholesterol efflux drives stem cell expansion in hypercholesterolaemia

Cholesterol efflux drives stem cell expansion in hypercholesterolaemia R E s E a RC h hI ghl I ghts h YPER t E n SIO n The primary end point was change in 24-h ambulatory systolic blood pressure between baseline and Lowering blood pressure in 6 months. Patients who received either black African patients of the combinations containing Dual therapies combining a population,” explains Dike Ojji, amlodipine had a larger reduction in calcium-channel blocker with an corresponding author. blood pressure than those patients angiotensin-converting enzyme In this trial, 728 black patients who received perindopril and A calcium- (ACE) inhibitor or thiazide diuretic with uncontrolled hypertension from hydrochlorothiazide. The efficacy channel are more effective at lowering blood six countries in sub-Saharan Africa of calcium-channel blockers as blocker pressure in black African patients were randomly assigned to receive monotherapy in black patients is well than the combination of an ACE amlodipine (a calcium-channel might also established, and the results from this inhibitor and a thiazide diuretic, blocker) and hydrochlorothiazide study suggest that a calcium-channel be the vital according to results presented at (a thiazide diuretic), amlodipine and blocker might also be the vital component in ACC.19. perindopril (an ACE inhibitor) or component in dual therapies. dual therapies Dual therapies are needed in perindopril and hydrochlorothiazide. “This study emphasizes the need many patients to control blood to establish optimal antihypertensive pressure effectively; however, combination therapies by ethnicity,” recommendations for combination says Ojji. “It would also be interesting therapies in black patients differ to carry out the same project in across three guidelines in the African Americans and compare USA and the latest European results as it is difficult to extrapolate guidelines. “We decided to do this our work to this population because research because before now no of gene–environment interaction and large randomized controlled trials genetic admixture.” have compared the efficacy of Isobel Leake contemporary combination therapies ORIgInAL AR tIcLE Ojji, D. B. et al. Comparison among any black populations, in spite of dual therapies for lowering blood pressure in Black Africans. N. Engl. J. Med. https://doi.org/ of the high burden of hypertension 10.1056/NEJMoa1901113 (2019) and its complications in this D YSLIPID AEMI A Cholesterol efflux drives stem cell expansion i n h yp er ch ol es terolaemia Hypercholesterolaemia induces Aibp2-mediated cholesterol efflux activates endothelial Srebp2, which in the expansion of haematopoietic stem and progenitor cells (HSPCs), turn transactivates the Notch pathway, promoting HSPC emergence. resulting in increased leukocyte numbers, which contribute to In Ldlr- knockout mice fed a high- The research team plans to continue cholesterol diet, inhibition of SreBP2 atherosclerotic cardiovascular disease. exploring the role of cholesterol However, the mechanisms linking repressed the hypercholesterolaemia- meta bolism in haematopoiesis. induced HSPC expansion in the bone hypercholesterolaemia and HSPC “Generation of autologous, bona fide expansion are unclear. Longhou Fang and marrow, suggesting that SreBP2- HSPCs is essential for regenerative SREBP2- regulated Notch signalling contributes colleagues describe a new mechanism medi cine, and our findings may for HSPC emergence in embryogenesis to HSPC expansion during hypercho- regulated bring us one step closer to this lesterolaemia in adults. Previous studies that also regulates adult haematopoiesis Notch ultimate goal,” highlights f ang. in hypercholesterolaemic conditions. in mice showed that SreBP2 inhibition “our studies also provide new signalling reduces atherosclerotic burden. The investigators show that during therapeutic targets for immunological embryogenesis in zebrafish, apolipopr otein “We speculate that SreBP2 suppression contributes and haematological diseases, as well as protects against cardiovascular A- I binding protein 2 (Aibp2; also known to HSPC for cardiovascular disease.” as Yjefn3) — a pro-haematopoietic cue disease in part by targeting aberrant Irene Fernández-​Ruiz expansion haematopoiesis,” explains f ang. derived from the somite that binds to HDl, which augments cholesterol efflux finally, the investigators confirmed ORIgInAL AR tIcLE Gu, Q. et al. AIBP- mediated during cholesterol efflux instructs hematopoietic stem and — increases HSPC specification from the the relevance of their findings in progenitor cell fate. Science 363, 1085–1088 (2019) hyperchole s- haemogenic endothelium through the humans, showing that increased FURthER READIng Rahman, M. S. et al. Effects activation of sterol regulatory element- terolaemia SreBP2 and Notch signalling activation of dyslipidaemia on monocyte production and function in cardiovascular disease. Nat. Rev. Cardiol. binding protein 2 (Srebp2), the master was associated with HSPC expansion in 14, 387–400 (2017) regulator of cholesterol biosynthesis. patients with hypercholesterolaemia. NA Ture r evIeWS | CArdioLogy volume 16 | J u N e 2019 | 323 Credit: V. Summersby/Springer Nature Limited Credit: V. Summersby/ Springer Nature Limited http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Reviews Cardiology Springer Journals

Cholesterol efflux drives stem cell expansion in hypercholesterolaemia

Nature Reviews Cardiology, Volume 16 (6) – Mar 29, 2019

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Publisher
Springer Journals
Copyright
Copyright © 2019 by Springer Nature Limited
ISSN
1759-5002
eISSN
1759-5010
D.O.I.
10.1038/s41569-019-0187-0
Publisher site
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Abstract

R E s E a RC h hI ghl I ghts h YPER t E n SIO n The primary end point was change in 24-h ambulatory systolic blood pressure between baseline and Lowering blood pressure in 6 months. Patients who received either black African patients of the combinations containing Dual therapies combining a population,” explains Dike Ojji, amlodipine had a larger reduction in calcium-channel blocker with an corresponding author. blood pressure than those patients angiotensin-converting enzyme In this trial, 728 black patients who received perindopril and A calcium- (ACE) inhibitor or thiazide diuretic with uncontrolled hypertension from hydrochlorothiazide. The efficacy channel are more effective at lowering blood six countries in sub-Saharan Africa of calcium-channel blockers as blocker pressure in black African patients were randomly assigned to receive monotherapy in black patients is well than the combination of an ACE amlodipine (a calcium-channel might also established, and the results from this inhibitor and a thiazide diuretic, blocker) and hydrochlorothiazide study suggest that a calcium-channel be the vital according to results presented at (a thiazide diuretic), amlodipine and blocker might also be the vital component in ACC.19. perindopril (an ACE inhibitor) or component in dual therapies. dual therapies Dual therapies are needed in perindopril and hydrochlorothiazide. “This study emphasizes the need many patients to control blood to establish optimal antihypertensive pressure effectively; however, combination therapies by ethnicity,” recommendations for combination says Ojji. “It would also be interesting therapies in black patients differ to carry out the same project in across three guidelines in the African Americans and compare USA and the latest European results as it is difficult to extrapolate guidelines. “We decided to do this our work to this population because research because before now no of gene–environment interaction and large randomized controlled trials genetic admixture.” have compared the efficacy of Isobel Leake contemporary combination therapies ORIgInAL AR tIcLE Ojji, D. B. et al. Comparison among any black populations, in spite of dual therapies for lowering blood pressure in Black Africans. N. Engl. J. Med. https://doi.org/ of the high burden of hypertension 10.1056/NEJMoa1901113 (2019) and its complications in this D YSLIPID AEMI A Cholesterol efflux drives stem cell expansion i n h yp er ch ol es terolaemia Hypercholesterolaemia induces Aibp2-mediated cholesterol efflux activates endothelial Srebp2, which in the expansion of haematopoietic stem and progenitor cells (HSPCs), turn transactivates the Notch pathway, promoting HSPC emergence. resulting in increased leukocyte numbers, which contribute to In Ldlr- knockout mice fed a high- The research team plans to continue cholesterol diet, inhibition of SreBP2 atherosclerotic cardiovascular disease. exploring the role of cholesterol However, the mechanisms linking repressed the hypercholesterolaemia- meta bolism in haematopoiesis. induced HSPC expansion in the bone hypercholesterolaemia and HSPC “Generation of autologous, bona fide expansion are unclear. Longhou Fang and marrow, suggesting that SreBP2- HSPCs is essential for regenerative SREBP2- regulated Notch signalling contributes colleagues describe a new mechanism medi cine, and our findings may for HSPC emergence in embryogenesis to HSPC expansion during hypercho- regulated bring us one step closer to this lesterolaemia in adults. Previous studies that also regulates adult haematopoiesis Notch ultimate goal,” highlights f ang. in hypercholesterolaemic conditions. in mice showed that SreBP2 inhibition “our studies also provide new signalling reduces atherosclerotic burden. The investigators show that during therapeutic targets for immunological embryogenesis in zebrafish, apolipopr otein “We speculate that SreBP2 suppression contributes and haematological diseases, as well as protects against cardiovascular A- I binding protein 2 (Aibp2; also known to HSPC for cardiovascular disease.” as Yjefn3) — a pro-haematopoietic cue disease in part by targeting aberrant Irene Fernández-​Ruiz expansion haematopoiesis,” explains f ang. derived from the somite that binds to HDl, which augments cholesterol efflux finally, the investigators confirmed ORIgInAL AR tIcLE Gu, Q. et al. AIBP- mediated during cholesterol efflux instructs hematopoietic stem and — increases HSPC specification from the the relevance of their findings in progenitor cell fate. Science 363, 1085–1088 (2019) hyperchole s- haemogenic endothelium through the humans, showing that increased FURthER READIng Rahman, M. S. et al. Effects activation of sterol regulatory element- terolaemia SreBP2 and Notch signalling activation of dyslipidaemia on monocyte production and function in cardiovascular disease. Nat. Rev. Cardiol. binding protein 2 (Srebp2), the master was associated with HSPC expansion in 14, 387–400 (2017) regulator of cholesterol biosynthesis. patients with hypercholesterolaemia. NA Ture r evIeWS | CArdioLogy volume 16 | J u N e 2019 | 323 Credit: V. Summersby/Springer Nature Limited Credit: V. Summersby/ Springer Nature Limited

Journal

Nature Reviews CardiologySpringer Journals

Published: Mar 29, 2019

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