Circulation Research, Vol 71, 503-510, Copyright © 1992 by American Heart Association

ARTICLES

Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor

M Lombes, ME Oblin, JM Gasc, EE Baulieu, N Farman and JP Bonvalet
INSERM U 33, Labhormones, Bicetre, France.

The presence of mineralocorticoid receptors (MRs) and their physicochemical characteristics were investigated in the heart and blood vessels of rabbits. Immunohistochemical methods using the monoclonal anti-idiotypic antibody H10E, which interacts with the steroid binding domain of MRs, revealed the presence of immunoreactive material in the heart and large blood vessels. In the heart, a positive staining was observed in myocytes and endothelial cells of atria and ventricles. In vessels, MRs were detected in the aorta and pulmonary artery. They were localized in endothelial and vascular smooth muscle cells. No staining was present in the small vascular bed, arterioles, and capillaries. In all these studies, the mineralocorticoid specificity of the staining was assessed by in situ competition experiments with aldosterone and RU486, a glucocorticoid antagonist. The presence of MRs in the heart and vessels was further demonstrated by specific aldosterone binding to one class of high affinity binding sites in the cytosol of the adrenalectomized rabbit heart (Kd, 0.25 nM; maximum MR concentration, 15-20 fmol/mg protein), whose mineralocorticoid specificity has been clearly established by competition studies. Sedimentation gradient analyses revealed that the cardiovascular MR is an 8.5S hetero-oligomer that includes the heat shock protein 90. The physicochemical characteristics of the cardiovascular MRs are virtually identical to those of the renal MRs. Altogether, our results clearly demonstrate the presence of MRs in the cardiovascular system. This supports the possibility of direct aldosterone actions in the heart and blood vessels.

This article has been cited by other articles:

				S. Viengchareun, P. Kamenicky, M. Teixeira, D. Butlen, G. Meduri, N. Blanchard-Gutton, C. Kurschat, A. Lanel, L. Martinerie, S. Sztal-Mazer, et al. Osmotic Stress Regulates Mineralocorticoid Receptor Expression in a Novel Aldosterone-Sensitive Cortical Collecting Duct Cell Line Mol. Endocrinol., December 1, 2009; 23(12): 1948 - 1962. [Abstract] [Full Text] [PDF]

				Y. Tada, K. T. Kitazato, T. Tamura, K. Yagi, K. Shimada, T. Kinouchi, J. Satomi, and S. Nagahiro Role of Mineralocorticoid Receptor on Experimental Cerebral Aneurysms in Rats Hypertension, September 1, 2009; 54(3): 552 - 557. [Abstract] [Full Text] [PDF]

				A. M. Dorrance Are Macrophages the Foot Soldiers in the War Waged by Aldosterone Against the Heart? Hypertension, September 1, 2009; 54(3): 451 - 453. [Full Text] [PDF]

				J. Yang and M. J Young The mineralocorticoid receptor and its coregulators J. Mol. Endocrinol., August 1, 2009; 43(2): 53 - 64. [Abstract] [Full Text] [PDF]

				A. J Rickard and M. J Young Corticosteroid receptors, macrophages and cardiovascular disease J. Mol. Endocrinol., June 1, 2009; 42(6): 449 - 459. [Abstract] [Full Text] [PDF]

				M. Caprio, B. G. Newfell, A. la Sala, W. Baur, A. Fabbri, G. Rosano, M. E. Mendelsohn, and I. Z. Jaffe Functional Mineralocorticoid Receptors in Human Vascular Endothelial Cells Regulate Intercellular Adhesion Molecule-1 Expression and Promote Leukocyte Adhesion Circ. Res., June 6, 2008; 102(11): 1359 - 1367. [Abstract] [Full Text] [PDF]

				T. Muto, N. Ueda, T. Opthof, T. Ohkusa, K. Nagata, S. Suzuki, Y. Tsuji, M. Horiba, J.-K. Lee, H. Honjo, et al. Aldosterone modulates If current through gene expression in cultured neonatal rat ventricular myocytes Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2710 - H2718. [Abstract] [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]

				B. Pitt and G. S. Pitt Added Benefit of Mineralocorticoid Receptor Blockade in the Primary Prevention of Sudden Cardiac Death Circulation, June 12, 2007; 115(23): 2976 - 2982. [Full Text] [PDF]

				I. Z. Jaffe, Y. Tintut, B. G. Newfell, L. L. Demer, and M. E. Mendelsohn Mineralocorticoid Receptor Activation Promotes Vascular Cell Calcification Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 799 - 805. [Abstract] [Full Text] [PDF]

				T. Ohtani, M. Ohta, K. Yamamoto, T. Mano, Y. Sakata, M. Nishio, Y. Takeda, J. Yoshida, T. Miwa, M. Okamoto, et al. Elevated cardiac tissue level of aldosterone and mineralocorticoid receptor in diastolic heart failure: beneficial effects of mineralocorticoid receptor blocker Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R946 - R954. [Abstract] [Full Text] [PDF]

				N. Z. Lu, S. E. Wardell, K. L. Burnstein, D. Defranco, P. J. Fuller, V. Giguere, R. B. Hochberg, L. McKay, J.-M. Renoir, N. L. Weigel, et al. International Union of Pharmacology. LXV. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Glucocorticoid, Mineralocorticoid, Progesterone, and Androgen Receptors Pharmacol. Rev., December 1, 2006; 58(4): 782 - 797. [Full Text] [PDF]

				H. Oberleithner, C. Riethmuller, T. Ludwig, V. Shahin, C. Stock, A. Schwab, M. Hausberg, K. Kusche, and H. Schillers Differential action of steroid hormones on human endothelium. J. Cell Sci., May 1, 2006; 119(Pt 9): 1926 - 1932. [Abstract] [Full Text] [PDF]

				K. Nagata, K. Obata, J. Xu, S. Ichihara, A. Noda, H. Kimata, T. Kato, H. Izawa, T. Murohara, and M. Yokota Mineralocorticoid Receptor Antagonism Attenuates Cardiac Hypertrophy and Failure in Low-Aldosterone Hypertensive Rats Hypertension, April 1, 2006; 47(4): 656 - 664. [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]

				A. Benetos, J. P. Gardner, M. Kimura, C. Labat, R. Nzietchueng, B. Dousset, F. Zannad, P. Lacolley, and A. Aviv Aldosterone and Telomere Length in White Blood Cells J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2005; 60(12): 1593 - 1596. [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]

				A. Ouvrard-Pascaud, Y. Sainte-Marie, J.-P. Benitah, R. Perrier, C. Soukaseum, A. N. D. Cat, A. Royer, K. Le Quang, F. Charpentier, S. Demolombe, et al. Conditional Mineralocorticoid Receptor Expression in the Heart Leads to Life-Threatening Arrhythmias Circulation, June 14, 2005; 111(23): 3025 - 3033. [Abstract] [Full Text] [PDF]

				S. J. Zieman, V. Melenovsky, and D. A. Kass Mechanisms, Pathophysiology, and Therapy of Arterial Stiffness Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 932 - 943. [Abstract] [Full Text] [PDF]

				I. Z. Jaffe and M. E. Mendelsohn Angiotensin II and Aldosterone Regulate Gene Transcription Via Functional Mineralocortocoid Receptors in Human Coronary Artery Smooth Muscle Cells Circ. Res., April 1, 2005; 96(6): 643 - 650. [Abstract] [Full Text] [PDF]

				A. Nishiyama, L. Yao, Y. Fan, M. Kyaw, N. Kataoka, K. Hashimoto, Y. Nagai, E. Nakamura, M. Yoshizumi, T. Shokoji, et al. Involvement of Aldosterone and Mineralocorticoid Receptors in Rat Mesangial Cell Proliferation and Deformability Hypertension, April 1, 2005; 45(4): 710 - 716. [Abstract] [Full Text] [PDF]

				A. Mahmud and J. Feely Review: Arterial stiffness and the renin-angiotensin-aldosterone system Journal of Renin-Angiotensin-Aldosterone System, September 1, 2004; 5(3): 102 - 108. [Abstract] [PDF]

				A. Mano, T. Tatsumi, J. Shiraishi, N. Keira, T. Nomura, M. Takeda, S. Nishikawa, S. Yamanaka, S. Matoba, M. Kobara, et al. Aldosterone Directly Induces Myocyte Apoptosis Through Calcineurin-Dependent Pathways Circulation, July 20, 2004; 110(3): 317 - 323. [Abstract] [Full Text] [PDF]

				I. Bossis, S. Nishimura, M. Muchow, and T. E. Porter Pituitary Expression of Type I and Type II Glucocorticoid Receptors during Chicken Embryonic Development and Their Involvement in Growth Hormone Cell Differentiation Endocrinology, July 1, 2004; 145(7): 3523 - 3531. [Abstract] [Full Text] [PDF]

				I. Mazak, A. Fiebeler, D. N. Muller, J.-K. Park, E. Shagdarsuren, C. Lindschau, R. Dechend, C. Viedt, B. Pilz, H. Haller, et al. Aldosterone Potentiates Angiotensin II-Induced Signaling in Vascular Smooth Muscle Cells Circulation, June 8, 2004; 109(22): 2792 - 2800. [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]

				H. Oberleithner, T. Ludwig, C. Riethmuller, U. Hillebrand, L. Albermann, C. Schafer, V. Shahin, and H. Schillers Human Endothelium: Target for Aldosterone Hypertension, May 1, 2004; 43(5): 952 - 956. [Abstract] [Full Text] [PDF]

				H. Oberleithner Unorthodox Sites and Modes of Aldosterone Action Physiology, April 1, 2004; 19(2): 51 - 54. [Abstract] [Full Text] [PDF]

				T.R. Uhrenholt, J. Schjerning, P.B. Hansen, R. Norregaard, B.L. Jensen, G.L. Sorensen, and O. Skott Rapid Inhibition of Vasoconstriction in Renal Afferent Arterioles by Aldosterone Circ. Res., December 12, 2003; 93(12): 1258 - 1266. [Abstract] [Full Text] [PDF]

				A. M. Feldman The emerging role of pharmacogenomics in the treatment of patients with heart failure Ann. Thorac. Surg., December 1, 2003; 76(6): S2246 - 2253. [Full Text] [PDF]

				M. Karmazyn, Q. Liu, X. T. Gan, B. J. Brix, and L. Fliegel Aldosterone Increases NHE-1 Expression and Induces NHE-1-Dependent Hypertrophy in Neonatal Rat Ventricular Myocytes Hypertension, December 1, 2003; 42(6): 1171 - 1176. [Abstract] [Full Text] [PDF]

				K E Warnes, C L Coulter, J S Robinson, and I C McMillen The effect of intrafetal infusion of metyrapone on arterial blood pressure and on the arterial blood pressure response to angiotensin II in the sheep fetus during late gestation J. Physiol., October 15, 2003; 552(2): 621 - 633. [Abstract] [Full Text] [PDF]

				M. Epstein Aldosterone receptor blockade and the role of eplerenone: evolving perspectives Nephrol. Dial. Transplant., October 1, 2003; 18(10): 1984 - 1992. [Full Text] [PDF]

				B. Pitt, C. T Stier Jr, and S. Rajagopalan Mineralocorticoid receptor blockade: new insights into the mechanism of action in patients with cardiovascular disease Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 164 - 168. [Abstract] [PDF]

				P. N. Chander, R. Rocha, J. Ranaudo, G. Singh, A. Zuckerman, and C. T. Stier Jr. Aldosterone Plays a Pivotal Role in the Pathogenesis of Thrombotic Microangiopathy in SHRSP J. Am. Soc. Nephrol., August 1, 2003; 14(8): 1990 - 1997. [Abstract] [Full Text] [PDF]

				W. Qin, A. E. Rudolph, B. R. Bond, R. Rocha, E. A.G. Blomme, J. J. Goellner, J. W. Funder, and E. G. McMahon Transgenic Model of Aldosterone-Driven Cardiac Hypertrophy and Heart Failure Circ. Res., July 11, 2003; 93(1): 69 - 76. [Abstract] [Full Text] [PDF]

				Q. Pu, M. F. Neves, A. Virdis, R. M. Touyz, and E. L. Schiffrin Endothelin Antagonism on Aldosterone-Induced Oxidative Stress and Vascular Remodeling Hypertension, July 1, 2003; 42(1): 49 - 55. [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]

				T.-Y. Chun, L. J. Bloem, and J. H. Pratt Aldosterone Inhibits Inducible Nitric Oxide Synthase in Neonatal Rat Cardiomyocytes Endocrinology, May 1, 2003; 144(5): 1712 - 1717. [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]

				M. M. Engler, M. B. Engler, D. M. Pierson, L. B. Molteni, and A. Molteni Effects of Docosahexaenoic Acid on Vascular Pathology and Reactivity in Hypertension Experimental Biology and Medicine, March 1, 2003; 228(3): 299 - 307. [Abstract] [Full Text] [PDF]

				S. Kasama, T. Toyama, H. Kumakura, Y. Takayama, S. Ichikawa, T. Suzuki, and M. Kurabayashi Effect of spironolactone on cardiacsympathetic nerve activity and left ventricular remodeling in patients with dilated cardiomyopathy J. Am. Coll. Cardiol., February 19, 2003; 41(4): 574 - 581. [Abstract] [Full Text] [PDF]

				D. L. Brutsaert Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity Physiol Rev, January 1, 2003; 83(1): 59 - 115. [Abstract] [Full Text] [PDF]

				J. D. Stockand and J. G. Meszaros Aldosterone stimulates proliferation of cardiac fibroblasts by activating Ki-RasA and MAPK1/2 signaling Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H176 - H184. [Abstract] [Full Text] [PDF]

				P. Lacolley, C. Labat, A. Pujol, C. Delcayre, A. Benetos, and M. Safar Increased Carotid Wall Elastic Modulus and Fibronectin in Aldosterone-Salt-Treated Rats: Effects of Eplerenone Circulation, November 26, 2002; 106(22): 2848 - 2853. [Abstract] [Full Text] [PDF]

				S. Neumann, K. Huse, R. Semrau, A. Diegeler, R. Gebhardt, G. H. Buniatian, and G. H. Scholz Aldosterone and D-Glucose Stimulate the Proliferation of Human Cardiac Myofibroblasts In Vitro Hypertension, March 1, 2002; 39(3): 756 - 760. [Abstract] [Full Text] [PDF]

				C. Ngarmukos and R. J. Grekin Nontraditional aspects of aldosterone physiology Am J Physiol Endocrinol Metab, December 1, 2001; 281(6): E1122 - E1127. [Abstract] [Full Text] [PDF]

				L. M.A.B. Van Bortel, H. A.J. Struijker-Boudier, and M. E. Safar Pulse Pressure, Arterial Stiffness, and Drug Treatment of Hypertension Hypertension, October 1, 2001; 38(4): 914 - 921. [Abstract] [Full Text] [PDF]

				J. B. Park and E. L. Schiffrin ETA Receptor Antagonist Prevents Blood Pressure Elevation and Vascular Remodeling in Aldosterone-Infused Rats Hypertension, June 1, 2001; 37(6): 1444 - 1449. [Abstract] [Full Text] [PDF]

				T. Tsutamoto, A. Wada, K. Maeda, N. Mabuchi, M. Hayashi, T. Tsutsui, M. Ohnishi, M. Sawaki, M. Fujii, T. Matsumoto, et al. Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure J. Am. Coll. Cardiol., April 1, 2001; 37(5): 1228 - 1233. [Abstract] [Full Text] [PDF]

				P. Lacolley, M. E. Safar, B. Lucet, K. Ledudal, C. Labat, and A. Benetos Prevention of aortic and cardiac fibrosis by spironolactone in old normotensive rats J. Am. Coll. Cardiol., February 1, 2001; 37(2): 662 - 667. [Abstract] [Full Text] [PDF]

				N. Farman and M.-E. Rafestin-Oblin Multiple aspects of mineralocorticoid selectivity Am J Physiol Renal Physiol, February 1, 2001; 280(2): F181 - F192. [Abstract] [Full Text] [PDF]

				M. Epstein Aldosterone as a determinant of cardiovascular and renal dysfunction J R Soc Med, January 8, 2001; 94(8): 378 - 383. [Full Text] [PDF]

				T. Tsutamoto, A. Wada, K. Maeda, N. Mabuchi, M. Hayashi, T. Tsutsui, M. Ohnishi, M. Sawaki, M. Fujii, T. Matsumoto, et al. Spironolactone inhibits the transcardiac extraction of aldosterone in patients with congestive heart failure J. Am. Coll. Cardiol., September 1, 2000; 36(3): 838 - 844. [Abstract] [Full Text] [PDF]

				K. M. Kayes-Wandover and P. C. White Steroidogenic Enzyme Gene Expression in the Human Heart J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2519 - 2525. [Abstract] [Full Text]

				D. Le Menuet, S. Viengchareun, P. Penfornis, F. Walker, M.-C. Zennaro, and M. Lombes Targeted Oncogenesis Reveals a Distinct Tissue-specific Utilization of Alternative Promoters of the Human Mineralocorticoid Receptor Gene in Transgenic Mice J. Biol. Chem., March 10, 2000; 275(11): 7878 - 7886. [Abstract] [Full Text] [PDF]

				J.-P. Benitah and G. Vassort Aldosterone Upregulates Ca2+ Current in Adult Rat Cardiomyocytes Circ. Res., December 3, 1999; 85(12): 1139 - 1145. [Abstract] [Full Text] [PDF]

				J.-S. Silvestre, V. Robert, C. Heymes, B. Aupetit-Faisant, C. Mouas, J.-M. Moalic, B. Swynghedauw, and C. Delcayre Myocardial Production of Aldosterone and Corticosterone in the Rat. PHYSIOLOGICAL REGULATION J. Biol. Chem., February 27, 1998; 273(9): 4883 - 4891. [Abstract] [Full Text] [PDF]

				A. S. Mihailidou, K. A. Buhagiar, and H. H. Rasmussen Na+ influx and Na+-K+ pump activation during short-term exposure of cardiac myocytes to aldosterone Am J Physiol Cell Physiol, January 1, 1998; 274(1): C175 - C181. [Abstract] [Full Text] [PDF]

				A. Benetos, P. Lacolley, and M.E. Safar Prevention of Aortic Fibrosis by Spironolactone in Spontaneously Hypertensive Rats Arterioscler Thromb Vasc Biol, June 1, 1997; 17(6): 1152 - 1156. [Abstract] [Full Text]

				M.-C. Zennaro, N. Farman, J.-P. Bonvalet, and M. Lombes Tissue-Specific Expression of {alpha} and {beta} Messenger Ribonucleic Acid Isoforms of the Human Mineralocorticoid Receptor in Normal and Pathological States J. Clin. Endocrinol. Metab., May 1, 1997; 82(5): 1345 - 1352. [Abstract] [Full Text] [PDF]

				Y. Shigematsu, M. Hamada, H. Okayama, Y. Hara, Y. Hayashi, K. Kodama, K. Kohara, and K. Hiwada Left Ventricular Hypertrophy Precedes Other Target-Organ Damage in Primary Aldosteronism Hypertension, March 1, 1997; 29(3): 723 - 727. [Abstract] [Full Text]

				V. Robert, J.-S. Silvestre, D. Charlemagne, A. Sabri, P. Trouve, M. Wassef, B. Swynghedauw, and C. Delcayre Biological Determinants of Aldosterone-Induced Cardiac Fibrosis in Rats Hypertension, December 1, 1995; 26(6): 971 - 978. [Abstract] [Full Text]

				M. Lombes, N. Alfaidy, E. Eugene, A. Lessana, N. Farman, and J.-P. Bonvalet Prerequisite for Cardiac Aldosterone Action : Mineralocorticoid Receptor and 11ß-Hydroxysteroid Dehydrogenase in the Human Heart Circulation, July 15, 1995; 92(2): 175 - 182. [Abstract] [Full Text]

				A. Nicoletti, D. Heudes, N. Hinglais, M.-D. Appay, M. Philippe, C. Sassy-Prigent, J. Bariety, and J.-B. Michel Left Ventricular Fibrosis in Renovascular Hypertensive Rats : Effect of Losartan and Spironolactone Hypertension, July 1, 1995; 26(1): 101 - 111. [Abstract] [Full Text]