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Friday, May 15, Broadway Ballroom, 8:00 AM: Plenary Session II: Awards Session

Friday, May 15, Broadway Ballroom, 8:00 AM: Plenary Session II: Awards Session A]H-APRIL 1998-VOL. 11, NO. 4, PART 2 238A ASHXIII ABSTRACTS Thursday, May 14, Astor Ballroom, 5:00 PM Thursday, May 14, Astor Ballroom, 5:00 PM Theme I: Biology of Hypertensive Vascular Theme I: Biology of Hypertensive Vascular Disease Disease Endothelial dysfunction in human hypertension and Hypertension and Changes in the Aordc Adventitia. Peter Brecher, Boston University School of Medicine. atherosclerosis. Mark A. Creager, M.D., Cardiovascular The effect of endothelial cellderived nitric oxide (NO) on Division, Brigham and Women’s Hospital, Harvard Medical underlying vascular smooth muscle is a well documented School, Bnston, Massachusetts example of paracrine regulation. The studies to bc described examine the possibility that the vascular adventitia is a source Among the important substances released by the of NO and that adventitial fibroblasts could influence vascular growth and function during the progression of hypertension. endothelium is nitric o~ide (NO) which regulates vascular A combination of in vivo and in vitro studies using aordc tone, mediates interaction between the vessel wall, platelets, rings and cultured aortic adverrtitiml fibroblasts was and leukocytes, and inhibits vascular smooth muscle growth performed. In siru hybridization showed iNOS rnRNA in the Endothelium-dependentrelaxation mediated by NO is endothelium and adventitia, but not in tbc media of aortic impaired in atherosclerotic vessels. Moreover, a variety of tissue following both in vivo and in vitro experiments. Cultured aortic adventitial fibroblasts, when incubated with atherosclerotic risk factors are associated with reduced cytokines, showed all the characteristics of iNOS induction. bioavailability of nitric oxide. These include hypertension, We also characterized the response of adventitial tibroblasts to hypercholesterolemia, diabetes, cigarette smoking, angiotensin II (ang II) and to NO. The cells proliferated hyperhomocysteinemia, and aging. These tindings suggest following in vivo treatment with ang 11 and cultured that reduced levels of NO may contribute to the fibroblaats were responsive to ang II with respect to activation of MAP kinases and DNA synthesis. NO was shown to development of atherosclerosis. Mechanisms through which reduce the proliferation of adventitial tibroblasts stimulated these risk factors may reduce the activity of nitric oxide with serum. Because the induction of p21, an inhibitor of include: insufficient L-arginine, impaired receptor-G cyclin-depadent kinases, rrright account for the protein signaling, reduced activity of NO synthase, and antiproliferativeeffects of NO, its expression was studied in inactivation of NO by a superoxide onion. Therapeutic serum-stimulated fibroblasts. Addition of NO donors either at interventions which restore endothelium-dependent quiescence or 15 h following serum addition induced a rapid (l-4 h) induction of p21 rnRNA. The increased expression of vasodilation include L-arginine supplementation, cholesterol p21 rnRNA during Jatc G] was rrrimickcdby addition of 8- reduction, arrgioterrsin-convertingenzyme inhibitors, bromo cGMP and effectively bluckcd by ODQ, a drug known smoking cessation, arrtioxidarrtsand estrogen replacement to inhibit the activation of soluble guarrylate cyclaxe by NO. therapy. Restoration ofendothelium-derived NO may Tbese studies indicate that the aortic adventitia is a petentid source of NO and implicate NO as a potential regulator of tfrc contribute to the cardiovascular benefits conferred by many cell cycle in aorfic adventitid fibroblaata through a cycfic of these therapies. GMP-mediated transcriptional mechanism involving the induction of p21. Key Words: nitric oxide, endothelium, atherosclerosis, Key Words: nitric Oxide. fibrObl~ts, cell cYcle,~giOtensin II superoxide, hypercholesterolemia Friday, May 15, Broadway Ballroom, 8:00 AM Friday, May 15, Broadway Ballroom, 8:00 AM Plenary Session II: Awards Session Plenary Session II: Awards Session Angiotensin I-ConvertingEnzyme(ACE): Sequence and TheASH SDeclal Lecture consequemes Comparison of the Effects of ACE Inhibitionand flLRecaotor Blockade on Atherosclerosis PierreCORVOL Aram V. Chobanian, M. D., Boston Univ. School of Medicine INSERMUnit36- CoU&ge de Frsnce-75005 PARIS - FRANCE ACE inhibitors have been shown to reduce the develop- ACE playsa centralrolein bloodpresswe (BP) regulation by ment of atherosclerosis in hyperchrdesterolemic animals acting on its classic physiological substrates, a“giotensi” I (AI@) across a wide range of species. Although the mechanism and bmdykinin (BK), The cloning ofh”mm ACE, 10 years aso, for these effects has not been well-delineated, it has gener- revealed the presmcx of two disti”ct iwforms. ‘t%. predominant isofonn, somatic ACE, is composed of two highly similar domains ally bBen assumed that both angiotensin O suppression and (N and C domains); another isofonn is exclusively expreswd in interference with the breakdown of bradykinin are involved. mature spermatides (germinal ACE). Both enzymes me anchored to To determine whether angiotensin II receptor blockade may the plasma membranewith the active site(s) exposedat the provide similar effects as those observed with ACE inhibi- extrcelldarsurface of thecell.Amlysisof the ACE geneshowed the tion, we examined the influence of irbesartan, an AT, recep- presence of an intron insertionideletion (IID) polymorphism. tor antagonist, rm aortic atherosclerosis in Watanabe herita- The discovery of the ACE gem structure led to several ble hyperlipidemic rabbits using the identical protocol that questiom which are being anmvercd: 1) SPxificity of the N- amd C- was employed in our prior studies involving angiotensin domains. Both ACE domains a= active, but exhibit timctional converting enzyme inhibitors. At a dose of irbesartan (30 diffemmes. N-Acetyl-Ser-Asp-Lys-Proli”e (AcSDKP), a regulatory mg/kg/day) which was selected because it appeared to fichx of hematopoiesis, is specifically cleaved by the N-domai”; 2) Design of ACE domain-specific inhibitors. [t is possible to block most of the presser effects of infused angiotensin in synthesize sp$citic i“ vitro inhibitors of the N-dmnaim Such an rabbits, no effect on atherosclerosis was observed. How- inhibitor should i“crea$.eplasma AcSDKP without dteri”g AngI md ever, a higher dose of irbesartan (75 mg/kg/day) caused BK metabolism and would be of potential value dwi”s similar reductions in blood pressure and aortic atherosclero- chemotherapy i“ the protection ofhenmpoietic stern cells. 3) Roled sis as seen in prior studies with ACE inhibitors. The de- germinal ACE, Mouse ACE gene imctivation by homologous crease in aortic intimal surface involvement with irbesartan recwnbimition rewlts in male h~ofeflility. The ACE substrate was from 38.9 i 3.8% in controls to 24.1 + 3.0% in the involved in fecomiaticm is still unk”ow” but we recently showed that treated group (p < 0.01). Aortic cholesterol content was germi”al and ancestral (insect) forms of ACE can cleave dibasic also significantly reduced in those animals (p < 0.02). The peptides from the C-twrninw ofprohonmmes. Gennimd ACE could therefore act as carboxypeptidase E fcf the trimmins of basic findings indicate that suppression of the renin-angiotensin dipeptides fromprohonnones gcnemted in malegermcells,4) Role system by AT, receptor blockade in a genetically hypercho. of the.mchoring domaimgemticdly-enginereed mice lackingthe C- Iestemlemic rabbit model causes comparable inhibition of domain haveaphenorype simihutothatof completely ACE-deticient aortic atherosclerosis as that achieved by ACE inhibition mice,showing thattissueACE is essential to the omtrol of BP. 5) and that a mild reduction of blood pressure induced by both ACE gene polymorphism. The DD genotypeis accompanied by a classes of agents may contribute to their antiathemsclerotic doubling of plasma and tiswlm ACE, Several association studies action in this model. have shown the predispsi”g mle of this gene vmimt in the development of cardiovascular andrenaldiseases. ethemsclerosis, ACE inhibition, angiotensin, Key Words: AT, receptor blockade Key Words: Reniri, Angiotemin, ACE, Bradykbdn http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Hypertension Oxford University Press

Friday, May 15, Broadway Ballroom, 8:00 AM: Plenary Session II: Awards Session

Chobanian, Aram V.
American Journal of Hypertension , Volume 11 (S3) – Apr 1, 1998
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Publisher
Oxford University Press
Copyright
© 1998 by the American Journal of Hypertension, Ltd.
ISSN
0895-7061
eISSN
1941-7225
DOI
10.1016/S0895-7061(97)91591-0
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Abstract

A]H-APRIL 1998-VOL. 11, NO. 4, PART 2 238A ASHXIII ABSTRACTS Thursday, May 14, Astor Ballroom, 5:00 PM Thursday, May 14, Astor Ballroom, 5:00 PM Theme I: Biology of Hypertensive Vascular Theme I: Biology of Hypertensive Vascular Disease Disease Endothelial dysfunction in human hypertension and Hypertension and Changes in the Aordc Adventitia. Peter Brecher, Boston University School of Medicine. atherosclerosis. Mark A. Creager, M.D., Cardiovascular The effect of endothelial cellderived nitric oxide (NO) on Division, Brigham and Women’s Hospital, Harvard Medical underlying vascular smooth muscle is a well documented School, Bnston, Massachusetts example of paracrine regulation. The studies to bc described examine the possibility that the vascular adventitia is a source Among the important substances released by the of NO and that adventitial fibroblasts could influence vascular growth and function during the progression of hypertension. endothelium is nitric o~ide (NO) which regulates vascular A combination of in vivo and in vitro studies using aordc tone, mediates interaction between the vessel wall, platelets, rings and cultured aortic adverrtitiml fibroblasts was and leukocytes, and inhibits vascular smooth muscle growth performed. In siru hybridization showed iNOS rnRNA in the Endothelium-dependentrelaxation mediated by NO is endothelium and adventitia, but not in tbc media of aortic impaired in atherosclerotic vessels. Moreover, a variety of tissue following both in vivo and in vitro experiments. Cultured aortic adventitial fibroblasts, when incubated with atherosclerotic risk factors are associated with reduced cytokines, showed all the characteristics of iNOS induction. bioavailability of nitric oxide. These include hypertension, We also characterized the response of adventitial tibroblasts to hypercholesterolemia, diabetes, cigarette smoking, angiotensin II (ang II) and to NO. The cells proliferated hyperhomocysteinemia, and aging. These tindings suggest following in vivo treatment with ang 11 and cultured that reduced levels of NO may contribute to the fibroblaats were responsive to ang II with respect to activation of MAP kinases and DNA synthesis. NO was shown to development of atherosclerosis. Mechanisms through which reduce the proliferation of adventitial tibroblasts stimulated these risk factors may reduce the activity of nitric oxide with serum. Because the induction of p21, an inhibitor of include: insufficient L-arginine, impaired receptor-G cyclin-depadent kinases, rrright account for the protein signaling, reduced activity of NO synthase, and antiproliferativeeffects of NO, its expression was studied in inactivation of NO by a superoxide onion. Therapeutic serum-stimulated fibroblasts. Addition of NO donors either at interventions which restore endothelium-dependent quiescence or 15 h following serum addition induced a rapid (l-4 h) induction of p21 rnRNA. The increased expression of vasodilation include L-arginine supplementation, cholesterol p21 rnRNA during Jatc G] was rrrimickcdby addition of 8- reduction, arrgioterrsin-convertingenzyme inhibitors, bromo cGMP and effectively bluckcd by ODQ, a drug known smoking cessation, arrtioxidarrtsand estrogen replacement to inhibit the activation of soluble guarrylate cyclaxe by NO. therapy. Restoration ofendothelium-derived NO may Tbese studies indicate that the aortic adventitia is a petentid source of NO and implicate NO as a potential regulator of tfrc contribute to the cardiovascular benefits conferred by many cell cycle in aorfic adventitid fibroblaata through a cycfic of these therapies. GMP-mediated transcriptional mechanism involving the induction of p21. Key Words: nitric oxide, endothelium, atherosclerosis, Key Words: nitric Oxide. fibrObl~ts, cell cYcle,~giOtensin II superoxide, hypercholesterolemia Friday, May 15, Broadway Ballroom, 8:00 AM Friday, May 15, Broadway Ballroom, 8:00 AM Plenary Session II: Awards Session Plenary Session II: Awards Session Angiotensin I-ConvertingEnzyme(ACE): Sequence and TheASH SDeclal Lecture consequemes Comparison of the Effects of ACE Inhibitionand flLRecaotor Blockade on Atherosclerosis PierreCORVOL Aram V. Chobanian, M. D., Boston Univ. School of Medicine INSERMUnit36- CoU&ge de Frsnce-75005 PARIS - FRANCE ACE inhibitors have been shown to reduce the develop- ACE playsa centralrolein bloodpresswe (BP) regulation by ment of atherosclerosis in hyperchrdesterolemic animals acting on its classic physiological substrates, a“giotensi” I (AI@) across a wide range of species. Although the mechanism and bmdykinin (BK), The cloning ofh”mm ACE, 10 years aso, for these effects has not been well-delineated, it has gener- revealed the presmcx of two disti”ct iwforms. ‘t%. predominant isofonn, somatic ACE, is composed of two highly similar domains ally bBen assumed that both angiotensin O suppression and (N and C domains); another isofonn is exclusively expreswd in interference with the breakdown of bradykinin are involved. mature spermatides (germinal ACE). Both enzymes me anchored to To determine whether angiotensin II receptor blockade may the plasma membranewith the active site(s) exposedat the provide similar effects as those observed with ACE inhibi- extrcelldarsurface of thecell.Amlysisof the ACE geneshowed the tion, we examined the influence of irbesartan, an AT, recep- presence of an intron insertionideletion (IID) polymorphism. tor antagonist, rm aortic atherosclerosis in Watanabe herita- The discovery of the ACE gem structure led to several ble hyperlipidemic rabbits using the identical protocol that questiom which are being anmvercd: 1) SPxificity of the N- amd C- was employed in our prior studies involving angiotensin domains. Both ACE domains a= active, but exhibit timctional converting enzyme inhibitors. At a dose of irbesartan (30 diffemmes. N-Acetyl-Ser-Asp-Lys-Proli”e (AcSDKP), a regulatory mg/kg/day) which was selected because it appeared to fichx of hematopoiesis, is specifically cleaved by the N-domai”; 2) Design of ACE domain-specific inhibitors. [t is possible to block most of the presser effects of infused angiotensin in synthesize sp$citic i“ vitro inhibitors of the N-dmnaim Such an rabbits, no effect on atherosclerosis was observed. How- inhibitor should i“crea$.eplasma AcSDKP without dteri”g AngI md ever, a higher dose of irbesartan (75 mg/kg/day) caused BK metabolism and would be of potential value dwi”s similar reductions in blood pressure and aortic atherosclero- chemotherapy i“ the protection ofhenmpoietic stern cells. 3) Roled sis as seen in prior studies with ACE inhibitors. The de- germinal ACE, Mouse ACE gene imctivation by homologous crease in aortic intimal surface involvement with irbesartan recwnbimition rewlts in male h~ofeflility. The ACE substrate was from 38.9 i 3.8% in controls to 24.1 + 3.0% in the involved in fecomiaticm is still unk”ow” but we recently showed that treated group (p < 0.01). Aortic cholesterol content was germi”al and ancestral (insect) forms of ACE can cleave dibasic also significantly reduced in those animals (p < 0.02). The peptides from the C-twrninw ofprohonmmes. Gennimd ACE could therefore act as carboxypeptidase E fcf the trimmins of basic findings indicate that suppression of the renin-angiotensin dipeptides fromprohonnones gcnemted in malegermcells,4) Role system by AT, receptor blockade in a genetically hypercho. of the.mchoring domaimgemticdly-enginereed mice lackingthe C- Iestemlemic rabbit model causes comparable inhibition of domain haveaphenorype simihutothatof completely ACE-deticient aortic atherosclerosis as that achieved by ACE inhibition mice,showing thattissueACE is essential to the omtrol of BP. 5) and that a mild reduction of blood pressure induced by both ACE gene polymorphism. The DD genotypeis accompanied by a classes of agents may contribute to their antiathemsclerotic doubling of plasma and tiswlm ACE, Several association studies action in this model. have shown the predispsi”g mle of this gene vmimt in the development of cardiovascular andrenaldiseases. ethemsclerosis, ACE inhibition, angiotensin, Key Words: AT, receptor blockade Key Words: Reniri, Angiotemin, ACE, Bradykbdn

Journal

American Journal of Hypertension – Oxford University Press

Published: Apr 1, 1998

There are no references for this article.