This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tea, B.-S. Articles by deBlois, D. Search for Related Content PubMed PubMed Citation Articles by Tea, B.-S. Articles by deBlois, D. Related Collections Remodeling Cardiovascular Pharmacology ACE/Angiotension receptors Animal models of human disease Apoptosis Hypertrophy Smooth muscle proliferation and differentiation

(Hypertension. 2000;35:1069.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Proapoptotic and Growth-Inhibitory Role of Angiotensin II Type 2 Receptor in Vascular Smooth Muscle Cells of Spontaneously Hypertensive Rats In Vivo

Bun-Seng Tea; Shant Der Sarkissian; Rhian M. Touyz; Pavel Hamet; Denis deBlois

From the Centre de Recherche, Centre Hospitaliér de l’Université de Montréal (CHUM) (B.-S. T., S.D.S., P.H., D.D.), Montreal, Quebec, Canada, and The Clinical Research Institute of Montreal (R.M.T.).

Correspondence to Denis deBlois, Centre de Recherche, CHUM–Hôtel-Dieu, 3840 St Urbain St, Room 7-132B, Montreal, Quebec H2W 1T8, Canada. E-mail debloisd{at}pharmco.umontreal.ca

Abstract—Angiotensin type 2 (AT₂) receptors for angiotensin II suppress cell growth and induce apoptosis in vitro, but their role is poorly defined in vivo. We reported that transient induction of smooth muscle cell (SMC) apoptosis precedes DNA synthesis inhibition and aortic hypertrophy regression in spontaneously hypertensive rats treated with the AT₁ antagonist losartan or the converting-enzyme inhibitor enalapril. Although both drugs are equipotent in reducing SMC number, apoptosis occurs significantly earlier with losartan than enalapril. To examine the role of AT₂ receptors in this model, spontaneously hypertensive rats were given valsartan, an AT₁ antagonist, or enalapril, in combination or not with the AT₂ antagonist PD123319 for 1 or 2 weeks. Control rats received vehicle. Systolic blood pressure was reduced similarly by valsartan and enalapril but it was not significantly affected by PD123319. Angiotensin II plasma levels were increased (6-fold) with valsartan and reduced (80%) with enalapril but unaffected by PD123319. Valsartan significantly increased internucleosomal DNA fragmentation indicative of apoptosis at 1 week only (2.7-fold) and significantly reduced aortic mass (18%), SMC number (33%), and DNA synthesis (24%, measured by ³H-thymidine incorporation) at 2 weeks. These valsartan-induced changes were prevented by PD123319. In contrast, enalapril-induced DNA fragmentation (2-fold increase at 2 weeks) was not affected by PD123319. PD123319 given alone did not affect growth or apoptosis. AT₁ and AT₂ receptor mRNAs were detected in the aorta by reverse transcription–polymerase chain reaction. Together, these results provide the first evidence that AT₂ receptors mediate vascular mass regression by stimulating SMC apoptosis in vivo, an effect seen during AT₁ receptor blockade but not during converting-enzyme inhibition.

Key Words: angiotensin II • muscle, smooth, vascular • losartan • enalapril

This article has been cited by other articles:

				E. I. Ager, J. Neo, and C. Christophi The renin-angiotensin system and malignancy Carcinogenesis, September 1, 2008; 29(9): 1675 - 1684. [Abstract] [Full Text] [PDF]

				E. Gurbanov and X. Shiliang The key role of apoptosis in the pathogenesis and treatment of pulmonary hypertension. Eur. J. Cardiothorac. Surg., September 1, 2006; 30(3): 499 - 507. [Abstract] [Full Text] [PDF]

				M. Paul, A. Poyan Mehr, and R. Kreutz Physiology of local Renin-Angiotensin systems. Physiol Rev, July 1, 2006; 86(3): 747 - 803. [Abstract] [Full Text] [PDF]

				R. I. Bechara, A. Pelaez, A. Palacio, P. C. Joshi, C. M. Hart, L. A. S. Brown, R. Raynor, and D. M. Guidot Angiotensin II mediates glutathione depletion, transforming growth factor-{beta}1 expression, and epithelial barrier dysfunction in the alcoholic rat lung Am J Physiol Lung Cell Mol Physiol, September 1, 2005; 289(3): L363 - L370. [Abstract] [Full Text] [PDF]

				J. Dutil, V. Eliopoulos, E.-L. Marchand, A. M. Devlin, J. Tremblay, K. Prithiviraj, P. Hamet, A. Migneault, D. deBlois, and A. Y. Deng A quantitative trait locus for aortic smooth muscle cell number acting independently of blood pressure: implicating the angiotensin receptor AT1B gene as a candidate Physiol Genomics, May 11, 2005; 21(3): 362 - 369. [Abstract] [Full Text] [PDF]

				L. M. Duke, R. G. Evans, and R. E Widdop AT2 receptors contribute to acute blood pressure-lowering and vasodilator effects of AT1 receptor antagonism in conscious normotensive but not hypertensive rats Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2289 - H2297. [Abstract] [Full Text] [PDF]

				E. L. Schiffrin and R. M. Touyz From bedside to bench to bedside: role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H435 - H446. [Full Text] [PDF]

				B. I. Levy Can Angiotensin II Type 2 Receptors Have Deleterious Effects in Cardiovascular Disease?: Implications for Therapeutic Blockade of the Renin-Angiotensin System Circulation, January 6, 2004; 109(1): 8 - 13. [Full Text] [PDF]

				S. Oparil, M. A. Zaman, and D. A. Calhoun Pathogenesis of Hypertension Ann Intern Med, November 4, 2003; 139(9): 761 - 776. [Full Text] [PDF]

				E.-L. Marchand, S. Der Sarkissian, P. Hamet, and D. deBlois Caspase-Dependent Cell Death Mediates the Early Phase of Aortic Hypertrophy Regression in Losartan-Treated Spontaneously Hypertensive Rats Circ. Res., April 18, 2003; 92(7): 777 - 784. [Abstract] [Full Text] [PDF]

				S. Der Sarkissian, E.-L. Marchand, D. Duguay, P. Hamet, and D. deBlois Reversal of interstitial fibroblast hyperplasia via apoptosis in hypertensive rat heart with valsartan or enalapril Cardiovasc Res, March 1, 2003; 57(3): 775 - 783. [Abstract] [Full Text] [PDF]

				R. E. Widdop, K. Matrougui, B. I. Levy, and D. Henrion AT2 Receptor-Mediated Relaxation Is Preserved After Long-Term AT1 Receptor Blockade Hypertension, October 1, 2002; 40(4): 516 - 520. [Abstract] [Full Text] [PDF]

				J. Suzuki, M. Iwai, H. Nakagami, L. Wu, R. Chen, T. Sugaya, M. Hamada, K. Hiwada, and M. Horiuchi Role of Angiotensin II-Regulated Apoptosis Through Distinct AT1 and AT2 Receptors in Neointimal Formation Circulation, August 13, 2002; 106(7): 847 - 853. [Abstract] [Full Text] [PDF]

				J.-S. Silvestre, R. Tamarat, T. Senbonmatsu, T. Icchiki, T. Ebrahimian, M. Iglarz, S. Besnard, M. Duriez, T. Inagami, and B. I. Levy Antiangiogenic Effect of Angiotensin II Type 2 Receptor in Ischemia-Induced Angiogenesis in Mice Hindlimb Circ. Res., May 31, 2002; 90(10): 1072 - 1079. [Abstract] [Full Text] [PDF]

				H. D. Intengan and E. L. Schiffrin Vascular Remodeling in Hypertension: Roles of Apoptosis, Inflammation, and Fibrosis Hypertension, September 1, 2001; 38(3): 581 - 587. [Abstract] [Full Text] [PDF]

				T.-X. Cui, H. Nakagami, M. Iwai, Y. Takeda, T. Shiuchi, L. Daviet, C. Nahmias, and M. Horiuchi Pivotal role of tyrosine phosphatase SHP-1 in AT2 receptor-mediated apoptosis in rat fetal vascular smooth muscle cell Cardiovasc Res, March 1, 2001; 49(4): 863 - 871. [Abstract] [Full Text] [PDF]