(Hypertension. 1999;33:981-986.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Angiotensin AT1 Receptor Subtype as a Cardiac Target of Aldosterone
Role in Aldosterone-Salt–Induced Fibrosis
From INSERM U127, IFR Lariboisière, Hôpital Lariboisière, Paris, France.
Correspondence to Claude Delcayre, U127-INSERM, Hôpital Lariboisière, 41 Bd de la Chapelle, 75475 Paris cedex 10, France. E-mail delcayre{at}infobiogen.fr
Abstract—This study tests the hypothesis that aldosterone induces cardiac fibrosis through an increase of cardiac angiotensin II (Ang II) AT1 receptor levels, thereby potentiating the fibrotic effect of Ang II by determining the effects of spironolactone and losartan on cardiac fibrosis, AT1 density, and gene expression in aldosterone-salt–treated rats. Fibrosis was quantified by slot blots of collagen I and III mRNA levels and videomorphometry of Sirius red–stained collagen. AT1 receptor density was determined by (125I-Sar1-Ile8)–Ang II competition binding, and AT1 mRNA levels were analyzed by quantitative reverse transcriptase polymerase chain reaction. One month of aldosterone-salt treatment induced a decrease in plasma Ang II and an increase in blood pressure, left ventricular hypertrophy, and ventricular fibrosis. Spironolactone (20 mg/kg per day) and losartan spironolactone (10 mg/kg per day) had no effect on the first 3 parameters. Losartan was as effective as spironolactone in preventing ventricular collagen mRNA increase and fibrosis. Ventricular density of AT1 receptors increased 2-fold and was accompanied by a 3-fold increase in the corresponding mRNA in aldosterone-salt compared with sham-operated rats. Both spironolactone and losartan prevented the elevation of ventricular AT1 density and that of right ventricular AT1 mRNA levels. These results demonstrate that the mechanism by which aldosterone-salt induces cardiac fibrosis involves Ang II acting through AT1 receptors. They also suggest that the cardiac AT1 receptor is a target for aldosterone.
Key Words: heart • aldosterone • angiotensin receptor • fibrosis
This article has been cited by other articles:
 |
|
 |
|
  T. Nakamura, K. Kataoka, M. Fukuda, H. Nako, Y. Tokutomi, Y.-F. Dong, H. Ichijo, H. Ogawa, and S. Kim-Mitsuyama Critical Role of Apoptosis Signal-Regulating Kinase 1 in Aldosterone/Salt-Induced Cardiac Inflammation and Fibrosis Hypertension, September 1, 2009; 54(3): 544 - 551. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Luther, Z. Wang, J. Ma, N. Makhanova, H.-S. Kim, and N. J. Brown Endogenous Aldosterone Contributes to Acute Angiotensin II-Stimulated Plasminogen Activator Inhibitor-1 and Preproendothelin-1 Expression in Heart But Not Aorta Endocrinology, May 1, 2009; 150(5): 2229 - 2236. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Wilkinson-Berka, G. Tan, K. Jaworski, and A. G. Miller Identification of a Retinal Aldosterone System and the Protective Effects of Mineralocorticoid Receptor Antagonism on Retinal Vascular Pathology Circ. Res., January 2, 2009; 104(1): 124 - 133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Diez Effects of Aldosterone on the Heart: Beyond Systemic Hemodynamics? Hypertension, September 1, 2008; 52(3): 462 - 464. [Full Text] [PDF]
|
|
|
|
 |
|
 A.C. Montezano, G.E. Callera, A. Yogi, Y. He, R.C. Tostes, G. He, E.L. Schiffrin, and R.M. Touyz Aldosterone and Angiotensin II Synergistically Stimulate Migration in Vascular Smooth Muscle Cells Through c-Src-Regulated Redox-Sensitive RhoA Pathways Arterioscler Thromb Vasc Biol, August 1, 2008; 28(8): 1511 - 1518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Yamada, M. Kushibiki, T. Osanai, H. Tomita, and K. Okumura Vasoconstrictor effect of aldosterone via angiotensin II type 1 (AT1) receptor: possible role of AT1 receptor dimerization Cardiovasc Res, July 1, 2008; 79(1): 169 - 178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z.-H. Zhang, Y. Yu, Y.-M. Kang, S.-G. Wei, and R. B. Felder Aldosterone acts centrally to increase brain renin-angiotensin system activity and oxidative stress in normal rats Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H1067 - H1074. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. J. Brown Aldosterone and Vascular Inflammation Hypertension, February 1, 2008; 51(2): 161 - 167. [Full Text] [PDF]
|
|
|
|
|
|
S. A. Cooper, A. Whaley-Connell, J. Habibi, Y. Wei, G. Lastra, C. Manrique, S. Stas, and J. R. Sowers Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2009 - H2023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Stas, A. Whaley-Connell, J. Habibi, L. Appesh, M. R. Hayden, P. R. Karuparthi, M. Qazi, E. M. Morris, S. A. Cooper, C. D. Link, et al. Mineralocorticoid Receptor Blockade Attenuates Chronic Overexpression of the Renin-Angiotensin-Aldosterone System Stimulation of Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase and Cardiac Remodeling Endocrinology, August 1, 2007; 148(8): 3773 - 3780. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Mejia-Vilet, V. Ramirez, C. Cruz, N. Uribe, G. Gamba, and N. A. Bobadilla Renal ischemia-reperfusion injury is prevented by the mineralocorticoid receptor blocker spironolactone Am J Physiol Renal Physiol, July 1, 2007; 293(1): F78 - F86. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Wong, F. E. Brennan, M. J. Young, P. J. Fuller, and T. J. Cole A Direct Effect of Aldosterone on Endothelin-1 Gene Expression in Vivo Endocrinology, April 1, 2007; 148(4): 1511 - 1517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Hirono, T. Yoshimoto, N. Suzuki, T. Sugiyama, M. Sakurada, S. Takai, N. Kobayashi, M. Shichiri, and Y. Hirata Angiotensin II Receptor Type 1-Mediated Vascular Oxidative Stress and Proinflammatory Gene Expression in Aldosterone-Induced Hypertension: The Possible Role of Local Renin-Angiotensin System Endocrinology, April 1, 2007; 148(4): 1688 - 1696. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Frias, M. C. Rebsamen, C. Gerber-Wicht, and U. Lang Prostaglandin E2 activates Stat3 in neonatal rat ventricular cardiomyocytes: A role in cardiac hypertrophy Cardiovasc Res, January 1, 2007; 73(1): 57 - 65. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Luther, J. V. Gainer, L. J. Murphey, C. Yu, D. E. Vaughan, J. D. Morrow, and N. J. Brown Angiotensin II Induces Interleukin-6 in Humans Through a Mineralocorticoid Receptor-Dependent Mechanism Hypertension, December 1, 2006; 48(6): 1050 - 1057. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Johar, A. C. Cave, A. Narayanapanicker, D. J. Grieve, and A. M. Shah Aldosterone mediates angiotensin II-induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase FASEB J, July 1, 2006; 20(9): 1546 - 1548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Nehme, N. Mercier, C. Labat, A. Benetos, M. E Safar, C. Delcayre, and P. Lacolley Differences Between Cardiac and Arterial Fibrosis and Stiffness in Aldosterone-Salt Rats: Effect of Eplerenone Journal of Renin-Angiotensin-Aldosterone System, March 1, 2006; 7(1): 31 - 39. [Abstract] [PDF]
|
|
|
|
 |
|
 T. R. Marcy and T. L. Ripley Aldosterone antagonists in the treatment of heart failure Am. J. Health Syst. Pharm., January 1, 2006; 63(1): 49 - 58. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Fuller and M. J. Young Mechanisms of Mineralocorticoid Action Hypertension, December 1, 2005; 46(6): 1227 - 1235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ishizawa, Y. Izawa, H. Ito, C. Miki, K. Miyata, Y. Fujita, Y. Kanematsu, K. Tsuchiya, T. Tamaki, A. Nishiyama, et al. Aldosterone Stimulates Vascular Smooth Muscle Cell Proliferation Via Big Mitogen-Activated Protein Kinase 1 Activation Hypertension, October 1, 2005; 46(4): 1046 - 1052. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.-J. Min, M. Mogi, J.-M. Li, J. Iwanami, M. Iwai, and M. Horiuchi Aldosterone and Angiotensin II Synergistically Induce Mitogenic Response in Vascular Smooth Muscle Cells Circ. Res., September 2, 2005; 97(5): 434 - 442. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ma, F. Albornoz, C. Yu, D. W. Byrne, D. E. Vaughan, and N. J. Brown Differing Effects of Mineralocorticoid Receptor-Dependent and -Independent Potassium-Sparing Diuretics on Fibrinolytic Balance Hypertension, August 1, 2005; 46(2): 313 - 320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Fraccarollo, P. Galuppo, I. Schmidt, G. Ertl, and J. Bauersachs Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction Cardiovasc Res, July 1, 2005; 67(1): 97 - 105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Xiao, J. R. Puddefoot, S. Barker, and G. P. Vinson Mechanism for Aldosterone Potentiation of Angiotensin II-Stimulated Rat Arterial Smooth Muscle Cell Proliferation Hypertension, September 1, 2004; 44(3): 340 - 345. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J E Macdonald, N Kennedy, and A D Struthers Effects of spironolactone on endothelial function, vascular angiotensin converting enzyme activity, and other prognostic markers in patients with mild heart failure already taking optimal treatment Heart, July 1, 2004; 90(7): 765 - 770. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Wang, S. Clement, G. Gabbiani, J.-D. Horisberger, M. Burnier, B. C. Rossier, and E. Hummler Chronic hyperaldosteronism in a transgenic mouse model fails to induce cardiac remodeling and fibrosis under a normal-salt diet Am J Physiol Renal Physiol, June 1, 2004; 286(6): F1178 - F1184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Michel, M.-L. Ambroisine, M. Duriez, C. Delcayre, B. I. Levy, and J.-S. Silvestre Aldosterone Enhances Ischemia-Induced Neovascularization Through Angiotensin II-Dependent Pathway Circulation, April 27, 2004; 109(16): 1933 - 1937. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. K Shieh, E. Kotlyar, and F. Sam Aldosterone and cardiovascular remodelling: focus on myocardial failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1): 3 - 13. [Abstract] [PDF]
|
|
|
|
 |
|
 D. Fraccarollo, P. Galuppo, S. Hildemann, M. Christ, G. Ertl, and J. Bauersachs Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction J. Am. Coll. Cardiol., November 5, 2003; 42(9): 1666 - 1673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Solomon and M. A. Pfeffer Aldosterone antagonism and myocardial infarction: From animals to man and back J. Am. Coll. Cardiol., November 5, 2003; 42(9): 1674 - 1676. [Full Text] [PDF]
|
|
|
|
|
|
B. Pitt, N. Reichek, R. Willenbrock, F. Zannad, R. A. Phillips, B. Roniker, J. Kleiman, S. Krause, D. Burns, and G. H. Williams Effects of Eplerenone, Enalapril, and Eplerenone/Enalapril in Patients With Essential Hypertension and Left Ventricular Hypertrophy: The 4E-Left Ventricular Hypertrophy Study Circulation, October 14, 2003; 108(15): 1831 - 1838. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Sawathiparnich, L. J. Murphey, S. Kumar, D. E. Vaughan, and N. J. Brown Effect of Combined AT1 Receptor and Aldosterone Receptor Antagonism on Plasminogen Activator Inhibitor-1 J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3867 - 3873. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. C. White Aldosterone: Direct Effects on and Production by the Heart J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2376 - 2383. [Full Text] [PDF]
|
|
|
|
|
|
N. J. Brown Eplerenone: Cardiovascular Protection Circulation, May 20, 2003; 107(19): 2512 - 2518. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Casal, J.-S. Silvestre, C. Delcayre, and A. M. Capponi Expression and Modulation of Steroidogenic Acute Regulatory Protein Messenger Ribonucleic Acid in Rat Cardiocytes and after Myocardial Infarction Endocrinology, May 1, 2003; 144(5): 1861 - 1868. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M MacKenzie, R. Fraser, J. M. Connell, and E. Davies Local renin-angiotensin systems and their interactions with extra-adrenal corticosteroid production Journal of Renin-Angiotensin-Aldosterone System, December 1, 2002; 3(4): 214 - 221. [Abstract] [PDF]
|
|
|
|
|
|
S. D. Solomon and M. A. Pfeffer Renin-Angiotensin System and Cardiac Rupture After Myocardial Infarction Circulation, October 22, 2002; 106(17): 2167 - 2169. [Full Text] [PDF]
|
|
|
|
|
|
A. S. Mihailidou, M. Mardini, J. W. Funder, and M. Raison Mineralocorticoid and Angiotensin Receptor Antagonism During Hyperaldosteronemia Hypertension, August 1, 2002; 40(2): 124 - 129. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Wang, E. Hummler, J. Nussberger, S. Clement, G. Gabbiani, H. R. Brunner, and M. Burnier Blood Pressure, Cardiac, and Renal Responses to Salt and Deoxycorticosterone Acetate in Mice: Role of Renin Genes J. Am. Soc. Nephrol., June 1, 2002; 13(6): 1509 - 1516. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Takeda, T. Yoneda, M. Demura, M. Usukura, and H. Mabuchi Calcineurin Inhibition Attenuates Mineralocorticoid-Induced Cardiac Hypertrophy Circulation, February 12, 2002; 105(6): 677 - 679. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hayashi, T. Tsutamoto, A. Wada, K. Maeda, N. Mabuchi, T. Tsutsui, T. Matsui, M. Fujii, T. Matsumoto, T. Yamamoto, et al. Relationship between transcardiac extraction of aldosterone and left ventricular remodeling in patients with first acute myocardial infarction: extracting aldosterone through the heart promotes ventricular remodeling after acute myocardial infarction J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1375 - 1382. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Foldes, M. Suo, I. Szokodi, Z. Lako-Futo, R. deChatel, O. Vuolteenaho, P. Huttunen, H. Ruskoaho, and M. Toth Factors Derived from Adrenals Are Required for Activation of Cardiac Gene Expression in Angiotensin II-Induced Hypertension Endocrinology, October 1, 2001; 142(10): 4256 - 4263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Peng, O. A. Carretero, M. E. Alfie, J. A. Masura, and N.-E. Rhaleb Effects of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Type 1 Receptor Antagonist in Deoxycorticosterone Acetate-Salt Hypertensive Mice Lacking Ren-2 Gene Hypertension, March 1, 2001; 37(3): 974 - 980. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Fiebeler, F. Schmidt, D. N. Muller, J.-K. Park, R. Dechend, M. Bieringer, E. Shagdarsuren, V. Breu, H. Haller, and F. C. Luft Mineralocorticoid Receptor Affects AP-1 and Nuclear Factor-{{kappa}}B Activation in Angiotensin II-Induced Cardiac Injury Hypertension, February 1, 2001; 37(2): 787 - 793. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. T Weber and Yao Sun Recruitable ACE and tissue repair in the infarcted heart Journal of Renin-Angiotensin-Aldosterone System, December 1, 2000; 1(4): 295 - 303. [PDF]
|
|
|
|
|
|
R. Rocha, C. T. Stier Jr., I. Kifor, M. R. Ochoa-Maya, H. G. Rennke, G. H. Williams, and G. K. Adler Aldosterone: A Mediator of Myocardial Necrosis and Renal Arteriopathy Endocrinology, October 1, 2000; 141(10): 3871 - 3878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. St. J. Sutton and N. Sharpe Left Ventricular Remodeling After Myocardial Infarction : Pathophysiology and Therapy Circulation, June 27, 2000; 101(25): 2981 - 2988. [Full Text] [PDF]
|
|
|
|
|
|
Q. N. Diep, M. El Mabrouk, P. Yue, and E. L. Schiffrin Effect of AT1 receptor blockade on cardiac apoptosis in angiotensin II-induced hypertension Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1635 - H1641. [Abstract] [Full Text] [PDF]
|
|