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Journal of Renin-Angiotensin-Aldosterone System
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Losartan-induced apoptosis as a novel mechanism for the prevention of vascular lesion formation after injury

Jacinthe Lemay

University of Montreal Hospital (CHUM) Research Center, Montreal, Quebec, Canada

Pavel Hamet

University of Montreal Hospital (CHUM) Research Center, Montreal, Quebec, Canada

Denis deBlois

University of Montreal Hospital (CHUM) Research Center, Montreal, Quebec, Canada, debloisd{at}pharmco.umontreal.ca

Smooth muscle cell (SMC) apoptosis is transiently increased at the onset of the regression of aortic hypertrophy in spontaneously hypertensive rats (SHR) treated with the angiotensin II AT1 antagonist losartan. We postulated that losartan induction of SMC apoptosis contributes to suppression of neointimal hyperplasia after vascular injury. Losartan or placebo treatment was initiated two days before balloon injury in the SHR aorta. Compared with time-matched placebo, losartan decreased neointimal cross-sectional area at Days 5 and 10 after injury by 50% and 64% respectively, without affecting medial mass. At Day 10, losartan significantly decreased SMC number (by 56%) in the neointima, but not in the media. DNA synthesis was significantly inhibited at Day 5 but not at Day 10. Losartan significantly increased aortic DNA fragmentation by 2.6- and 4.1-fold, at Days 5 and 10, respectively. In situ labeling of SMC with terminal deoxynucleotidyltransferase revealed significant 61% and 68% increases in apoptotic SMC at Days 5 and 10 with losartan treatment, predominantly in the neointima. Thus, losartan suppressed neointima formation in part by the induction of SMC apoptosis, which may be dissociated from the inhibition of DNA synthesis. Therefore, losartan-induced SMC apoptosis may be a potential therapeutic approach to control occlusive vascular disorders.

Key Words: vascular injury;AT1 antagonist • SHR aorta • apoptosis • smooth muscle cell

References

  • Nozawa Y., Matsuura N., Miyake H.,Yamada S., Kimura R. Effects of TH-142177 on angiotensin II-induced proliferation, migration and intracellular signalling in vascular smooth muscle cells and on neointimal thickening after balloon injury. Life Sci 1999;64(22):2061-70.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Stoll M., Steckelings UM, Paul M., Bottari SP, Metzger R., Unger T. The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest 1995;95(2):651-7.[Web of Science][Medline] [Order article via Infotrieve]
  • Bunkenburg B., van Amelsvoort T., Rogg H., Wood JM Receptor-mediated effects of angiotensin II on growth of vascular smooth muscle cells from spontaneously hypertensive rats. Hypertension 1992;20(6):746-54.[Abstract/Free Full Text]
  • Makita S., Nakamura M.,Yoshida H., Hiramori K. Effect of angiotensin II receptor blocker on angiotensin II stimulated DNA synthesis of cultured human aortic smooth muscle cells. Life Sci 1995;56(20):PL383-8.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Herbert JM, Delisee C., Dol F. et al. Effect of SR 47436, a novel angiotensin II AT1 receptor antagonist, on human vascular smooth muscle cells in vitro. Eur J Pharmacol 1994;251(2-3):143-50.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Kauffman RF, Bean JS, Zimmerman KM, Brown RF, Steinberg MI Losartan, a non-peptide angiotensin II (Ang II) receptor antagonist, inhibits neointima formation following balloon injury to rat carotid arteries. Life Sci 1991;49(25):PL223-8.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Prescott MF, Webb RL, Reidy MA Angiotensin-converting enzyme inhibitor versus angiotensin II, AT1-receptor antagonist. Effect on smooth muscle cell migration and proliferation after balloon catheter injury. Am J Pathol 1991;139: 1291-96.[Abstract]
  • Pham D., Laporte S., Pérodin J., Bourgeois R., Escher E. What can angiotensin antagonists do that converting-enzyme inhibition can't: the case of post-angioplastic restenosis. Canadian Journal of Physiological Pharmacology 1996;74:867-77.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Fukuyama J., Ichikawa K., Miyazawa K., Hamano S., Shibata N., Ujiie A. Tranilast suppresses intimal hyperplasia in the balloon injury model and cuff treatment model in rabbits. Jpn J Pharmacol 1996;70(4):321-7.[Medline] [Order article via Infotrieve]
  • Kawamura M.,Terashita Z., Okuda H. et al.TCV-116, a novel angiotensin II receptor antagonist, prevents intimal thickening and impairment of vascular function after carotid injury in rats. J Pharmacol Exp Ther 1993;266(3):1664-9.[Abstract/Free Full Text]
  • Taguchi J.,Abe J., Okazaki H. et al.Angiotensin converting enzyme inhibitors or DUP753 prevent neointimal formation following balloon injury with single topical or multiple systemic application. Biochem Biophys Res Commun 1993;196(2):969-74.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Taguchi J.,Abe J., Ohno M., Schwartz SM, Kurokawa K. Topical application of AT1-r receptor antagonists prevents medial and neointimal proliferation after balloon injury. Blood Press Suppl 1994;5:38-42.[Medline] [Order article via Infotrieve]
  • Matsuno H., Kozawa O., Niwa M., Kaida T., Hayashi H., Uematsu T. GR144053, a fibrinogen receptor antagonist, enhances the suppression of neointima formation by losartan, an angiotensin II receptor antagonist, in the injured carotid artery of hamster. British Journal of Pharmacology 1997;122:1099-1104.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • van Kleef EM, Fingerle J., Daemen MJ. Angiotensin II-induced progression of neointimal thickening in the balloon-injured rat carotid artery is AT1-receptor mediated. Arterioscler Thromb Vasc Biol 1996;16(7):857-63.[Abstract/Free Full Text]
  • deBlois D.,Tea BS,Than VD,Tremblay J., Hamet P. Smooth muscle apoptosis during vascular regression in spontaneously hypertensive rats. Hypertension 1997;29(1 Pt 2):340-9.[Abstract/Free Full Text]
  • Capron L., Heudes D., Chajara A., Bruneval P. Effect of ramipril, an inhibitor of angiotensin-converting enzyme, on the response of rat thoracic aorta injury with a balloon catheter. J Cardiovasc Pharmacol 1991;18:207-211.[Web of Science][Medline] [Order article via Infotrieve]
  • deBlois D., Viswanathan M., Su JE, Clowes AW, Saavedra JM, Schwartz SM Smooth muscle DNA replication in response to angiotensin II is regulated differently in the neointima and media at different times after balloon injury in the rat carotid artery. Role of AT1-receptor expression. Arterioscler Thromb Vasc Biol 1996;16(9):1130-7. 18. Teiger E., Dam TV, Richard L. et al. Apoptosis in pressure overload-induced heart hypertrophy in the rat. J Clin Invest 1996;97:2891-2897.[Web of Science][Medline] [Order article via Infotrieve]
  • Bochaton-Piallat ML, Gabbiani F., Redard M., Desmouliere A., Gabbiani G.Apoptosis participates in cellularity regulation during rat aortic intimal thickening. Am J Pathol 1995;146(5):1059-64.[Abstract]
  • Han DK, Haudenschild CC, Hong MK,Tinkle BT, Leon MB, Liau G. Evidence for apoptosis in human atherogenesis and in a rat vascular injury model [see comments]. Am J Pathol 1995;147(2):267-77.[Abstract]
  • Schwartz SM, deBlois D., O'Brien ER The intima. Soil for athrosclerosis and restenosis. Circulation Research 1995;77:445-465.[Free Full Text]
  • ClowesAW, Clowes MM, Reidy MA Kinetics of cellular proliferation after arterial injury. I. Smooth muscle growth in the absence of endothelium. Laboratory Investigation 1983;49:327-33.[Web of Science][Medline] [Order article via Infotrieve]
  • Tea BS, DamTV, Moreau P.,Hamet P.,deBlois D. Apoptosis during regression of cardiac hypertrophy in spontaneously hypertensive rats. Temporal regulation and spatial heterogeneity. Hypertension 1999;34(2):229-35.[Abstract/Free Full Text]
  • Diez J., Fortuno MA, Ravassa S. Apoptosis in hypertensive heart disease. Current Opinion in Cardiology 1998;13:317-25.[Web of Science][Medline] [Order article via Infotrieve]
  • Haunstetter A., Izumo S. Apoptosis: basic mechanisms and implications for cardiovascular disease. Circulation Research 1998;82:1111-29.[Free Full Text]
  • Igase M., Okura T., Kitami Y., Hiwada K. Apoptosis and Bcl-xs in the intimal thickening of balloon-injured carotid arteries. Clin Sci (Colch) 1999;96(6):605-12.[Medline] [Order article via Infotrieve]
  • Perlman H., Maillard L., Krasinski K., Walsh K. Evidence for the rapid onset of apoptosis in medial smooth muscle cells after balloon injury. Circulation 1997;95:981-7.[Abstract/Free Full Text]
  • Bauriedel G., Schluckebier S., Hutter R. et al.Apoptosis in restenosis versus stable-angina atherosclerosis: implications for the pathogenesis of restenosis. Arteriosclerosis, Thrombosis and Vascular Biology 1998;18:1132-39.
  • Ihling C., Haendeler J.,Menzel G. et al. Co-expression of p53 and MDM2 in human atherosclerosis: implications for the regulation of cellularity of atherosclerotic lesions. J Pathol 1998;185(3):303-12.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • KockxMM,De Meyer GR, Muhring J., Jacob W., Bult H., Herman AG Apoptosis and related proteins in different stages of human atherosclerotic plaques. Circulation 1998;97(23):2307-15.[Abstract/Free Full Text]
  • Bjorkerud S., Bjorkerud B. Apoptosis is abundant in human atherosclerotic lesions, especially in inflammatory cells (macrophages and T cells), and may contribute to the accumulation of gruel and plaque instability [see comments]. Am J Pathol 1996;149(2):367-80.[Abstract]
  • Geng YJ, Libby P. Evidence for apoptosis in advanced human atheroma. Colocalization with interleukin-1 beta-converting enzyme [see comments]. Am J Pathol 1995;147(2):251-66.[Abstract]
  • Jonasson L., Holm J., Hansson GK Smooth muscle cells express Ia antigens during arterial response to injury. Lab Invest 1988;58; 310-5.[Web of Science][Medline] [Order article via Infotrieve]
  • Pollman MJ,Yamada T., Horiuchi M., Gibbons GH Vasoactive substances regulate vascular smooth muscle apoptosis: countervailing influences of nitric oxide and angiotensin II. Circulation Research 1996;79:748-56.[Abstract/Free Full Text]
  • Tea BS, Der Sarkissian S.,Touyz RM, Hamet P.,deBlois D. Proapoptotic and growth inhibitory role of angiotensin II type 2 receptor in vascular smooth muscle cells of spontaneously hypertensive rats in vivo. Hypertension 2000;(in press).
  • Hutchinson HG, Hein L., Fujinaga M., Pratt RE Modulation of vascular development and injury by angiotensin II. Cardiovascular Research 1999;41:689-700.[Abstract/Free Full Text]
  • Bayer IM, Adamson SL, Langille BL Atrophic remodeling of the artery-cuffed artery. Arterioscler Thromb Vasc Biol 1999;19:1499-505.[Abstract/Free Full Text]
  • Pollman MJ, Hall JL,Mann MJ,Zhang L., Gibbons GH Inhibition of neointimal cell bcl-x expression induces apoptosis and regression of vascular disease. Nat Med 1998;4(2):222-7.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Wang BY, Ho HK, Lin PS et al. Regression of atherosclerosis: role of nitric oxide and apoptosis. Circulation 1999;99(9):1236-41.[Abstract/Free Full Text]

Journal of Renin-Angiotensin-Aldosterone System, Vol. 1, No. 1, 46-50 (2000)
DOI: 10.3317/jraas.2000.010
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