ABSTRACT Aldosterone antagonists have been reported to prevent ventricular remodeling after myocardial infarction (MI) _via_ their action to extracellular matrix (ECM). However, it remains

largely unknown whether aldosterone antagonists attenuate myocyte loss in the remodeling process. The present study examined whether spironolactone prevents myocyte apoptosis and improves

post-infarct ventricular remodeling in rats. MI was achieved by permanent occlusion of the left coronary artery. Administration of spironolactone (100 mg/kg/day) was started immediately

after MI. Sprague-Dawley rats were divided into four groups: 1) sham, 2) spironolactone-treated sham, 3) untreated MI, 4) spironolactone-treated MI. Echocardiographic parameters (left

untreated MI group. Moreover, the percentage of apoptotic myocytes evaluated by terminal deoxynucleotide transferase–mediated dUTP nick end labeling (TUNEL) assay was significantly lower in

the spironolactone-treated MI group on the 2nd (3.54% _vs_. 5.79% in untreated MI group), 7th (0.65% _vs_. 1.37% in untreated MI group) and 14th days (0.11% _vs_. 0.16% in untreated MI

group). Real time reverse transcription–polymerase chain reaction (RT-PCR) analysis showed that the expression of mineralocorticoid receptor (MR) mRNA and that of 11_β_-hydroxysteroid

dehydrogenase 2 (11_β_-HSD2) mRNA, which is known to confer aldosterone selectivity on MR, were upregulated in the untreated MI group, and that spironolactone significantly suppressed the

expression of these genes. Moreover, spironolactone significantly inhibited aldosterone-induced apoptosis in cultured rat cardiac myocytes in a dose-dependent fashion. Our study demonstrates

that, in addition to their effect on ECM, aldosterone antagonists inhibit myocyte apoptosis and prevent post-infarct ventricular remodeling by modulating the expression levels of MR and

11_β_-HSD2, which are enhanced in the remodeling heart. SIMILAR CONTENT BEING VIEWED BY OTHERS SUPPRESSING THE EXPRESSION OF STEROIDOGENIC ACUTE REGULATORY PROTEIN (STAR) IN THE MYOCARDIUM

BY SPIRONOLACTONE CONTRIBUTES TO THE IMPROVEMENT OF RIGHT VENTRICULAR REMODELING IN PULMONARY ARTERIAL HYPERTENSION Article 04 October 2024 LONG-TERM ADMINISTRATION OF RECOMBINANT CANSTATIN

PREVENTS ADVERSE CARDIAC REMODELING AFTER MYOCARDIAL INFARCTION Article Open access 30 July 2020 INHIBITION OF THE CANONICAL WNT SIGNALING PATHWAY BY A Β-CATENIN/CBP INHIBITOR PREVENTS HEART

FAILURE BY AMELIORATING CARDIAC HYPERTROPHY AND FIBROSIS Article Open access 21 July 2021 ARTICLE PDF REFERENCES * Pfeffer MA : Left ventricular remodeling after acute myocardial

infarction. _Annu Rev Med_ 1995; 46: 455–466. Article  CAS  Google Scholar  * Tatsumi T, Shiraishi J, Keira N, _et al_: Intracellular ATP is required for mitochondrial apoptotic pathways in

isolated hypoxic rat cardiac myocytes. _Cardiovasc Res_ 2003; 52: 428–440. Article  Google Scholar  * Fliss H, Gattinger D : Apoptosis in ischemic and reperfused rat myocardium. _Circ Res_

1996; 79: 949–956. Article  CAS  Google Scholar  * Kajstura J, Cheng W, Reiss K, _et al_: Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in

rats. _Lab Invest_ 1996; 74: 86–107. CAS  Google Scholar  * Cheng W, Kajstura J, Nitahara JA, _et al_: Programmed myocyte cell death affects the viable myocardium after infarction in rats.

_Exp Cell Res_ 1996; 226: 316–327. Article  CAS  Google Scholar  * Olivetti G, Quaini F, Sala R, _et al_: Acute myocardial infarction in humans is associated with the activation of

programmed myocyte cell death in the surviving portion of the heart. _J Mol Cell Cardiol_ 1996; 28: 2005–2016. Article  CAS  Google Scholar  * Beltrami CA, Finato N, Rocco M, _et al_:

Structural basis of end-stage failure in ischemic cardiomyopathy in humans. _Circulation_ 1994; 89: 151–163. Article  CAS  Google Scholar  * Olivetti G, Abbi R, Quaini F, _et al_: Apoptosis

in the failing human heart. _N Eng J Med_ 1997; 336: 1131–1141. Article  CAS  Google Scholar  * Saraste A, Pulkki K, Kallajoki M, _et al_: Cardiomyocyte apoptosis and progression of heart

failure to transplantation. _Eur J Clin Invest_ 1999; 29: 380–386. Article  CAS  Google Scholar  * Packer M : The neurohormonal hypothesis: a theory to explain the mechanism of disease

progression in heart failure. _J Am Coll Cardiol_ 1992; 20: 248–254. Article  CAS  Google Scholar  * Sato A, Saruta T : Aldosterone-induced organ damage: plasma aldosterone level and

inappropriate salt status. _Hypertens Res_ 2004; 27: 303–310. Article  CAS  Google Scholar  * Pitt B, Zannad F, Remme WJ, _et al_: The effect of spironolactone on morbidity and mortality in

patients with severe heart failure. _N Engl J Med_ 1999; 341: 709–717. Article  CAS  Google Scholar  * Pitt B, Remme W, Zannad F, _et al_, Eplerenone Post-Acute Myocardial Infarction Heart

Failure Efficacy and Survival Study Investigators : Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. _N Engl J Med_

2003; 348: 1309–1321. Article  CAS  Google Scholar  * Mizuno Y, Yoshimura M, Yasue H, _et al_: Aldosterone production is activated in the failing ventricles in human. _Circulation_ 2001;

103: 72–77. Article  CAS  Google Scholar  * Yamamoto N, Yasue H, Mizuno Y, _et al_: Aldosterone is produced from ventricles in patients with essential hypertension. _Hypertension_ 2002; 39:

958–962. Article  CAS  Google Scholar  * Silvestre JS, Robert V, Heymes C, _et al_: Myocardial production of aldosterone and corticosterone in the rat: physiological regulation. _J Biol

Chem_ 1998; 273: 4883–4891. Article  CAS  Google Scholar  * Struthers AD, MacDonald TM : Review of aldosterone-and angiotensin II–induced target organ damage and prevention. _Cardiovasc Res_

2004; 61: 663–670. Article  CAS  Google Scholar  * Funder JW : Glucocorticoid and mineralocorticoid receptors: biology and clinical relevance. _Annu Rev Med_ 1997; 48: 231–240. Article  CAS

  Google Scholar  * Slight SH, Ganjam VK, Gomez-Sanchez CE, Zhou MY, Weber KT : High affinity NAD+-dependent 11β-hydroxysteroid dehydrogenase in the human heart. _J Mol Cell Cardiol_ 1996;

28: 781–787. Article  CAS  Google Scholar  * Mano A, Tatsumi T, Shiraishi J, _et al_: Aldosterone directly induces myocyte apoptosis through calcineurin-dependent pathways. _Circulation_

2004; 110: 317–323. Article  CAS  Google Scholar  * Kobara M, Tatsumi T, Kambayashi D, _et al_: Effect of ACE inhibition on myocardial apoptosis in an ischemia-reperfusion rat heart model.

_J Cardiovasc Pharmacol_ 2003; 41: 880–889. Article  CAS  Google Scholar  * Veliotes DGA, Woodiwiss AJ, Deftereos DAJ, Gray D, Osadchii O, Norton GR : Aldosterone receptor blockade prevents

the transition to cardiac pump dysfunction induced by β-adrenoreceptor activation. _Hypertension_ 2005; 45: 914–920. Article  CAS  Google Scholar  * Bäcklund T, Palojoki E, Saraste A, _et

al_: Effect of vasopeptide inhibitor omapatrilat on cardiomyocyte apoptosis and ventricular remodeling in rat myocardial infarction. _Cardiovasc Res_ 2003; 57: 727–737. Article  Google

Scholar  * Delyani JA, Robinson EL, Rudolph AE : Effect of a selective aldosterone receptor antagonist in myocardial infarction. _Am J Physiol_ 2001; 50: H647–H654. Google Scholar  * Brilla

CG, Pick R, Tan LB, Janicki JS, Weber KT : Remodeling of the rat right and left ventricles in experimental hypertension. _Circ Res_ 1990; 67: 1355–1364. Article  CAS  Google Scholar  *

Roussoulieres AL, Raisky O, Chalabreysse L, _et al_: Identification and characterization of two genes (MIP-1β, VE-CADHERIN) implicated in acute rejection in human heart transplantation: use

of murine models in tandem with cDNA arrays. _Circulation_ 2005; 111: 2636–2644. Article  CAS  Google Scholar  * Delcayre C, Swynghedauw B : Molecular mechanisms of myocardial remodeling.

The role of aldosterone. _J Mol Cell Cardiol_ 2002; 34: 1577–1584. Article  CAS  Google Scholar  * Solomon SD, Pfeffer MA : Aldosterone antagonism and myocardial infarction. From animals to

man and back. _J Am Coll Cardiol_ 2003; 42: 1674–1676. Article  Google Scholar  * Zannad F, Alla F, Dousset B, Perez A, Pitt B, RALES Investigators : Limitation of excessive extracellular

matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the Randomized Aldactone Evaluation Study (RALES).

_Circulation_ 2000; 102: 2700–2706. Article  CAS  Google Scholar  * Suzuki G, Morita H, Mishima T, _et al_: Effects of long-term monotherapy with eplerenone, a novel aldosterone blocker, on

progression of left ventricular dysfunction and remodeling in dogs with heart failure. _Circulation_ 2002; 106: 2967–2972. Article  CAS  Google Scholar  * Fraccarollo D, Galuppo P, Hildemann

S, Christ M, Ertl G, Bauersachs J : 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_ 2003; 42: 1666–1673. Article  CAS  Google Scholar  * Hayakawa K, Takemura G, Kanoh M, _et al_: Inhibition of granulation tissue cell

apoptosis during the subacute stage of myocardial infarction improves cardiac remodeling and dysfunction at the chronic stage. _Circulation_ 2003; 108: 104–109. Article  Google Scholar  *

Wencker D, Chandra M, Nguyen K, _et al_: A mechanistic role for cardiac myocyte apoptosis in heart failure. _J Clin Invest_ 2003; 111: 1497–1504. Article  CAS  Google Scholar  * Foo RSY,

Mani K, Kitsis RN : Death begets failure in the heart. _J Clin Invest_ 2005; 115: 565–571. Article  CAS  Google Scholar  * Cesselli D, Jakoniuk I, Barlucchi L, _et al_: Oxidative

stress–mediated cardiac cell death is a major determinant of ventricular dysfunction and failure in dog dilated cardiomyopathy. _Circ Res_ 2001; 89: 279–286. Article  CAS  Google Scholar  *

Chandrashekhar Y, Sen S, Anway R, Shuros A, Anand I : Long-term caspase inhibition ameliorates apoptosis, reduces myocardial troponin-I cleavage, protects left ventricular function, and

attenuates remodeling in rats with myocardial infarction. _J Am Coll Cardiol_ 2004; 43: 295–301. Article  CAS  Google Scholar  * Leri A, Claudio PP, Li Q, _et al_: Stretch-mediated release

of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell. _J Clin Invest_ 1998;

101: 1326–1342. Article  CAS  Google Scholar  * de Gasparo M, Joss U, Ramjoue HP, _et al_: Three new epoxy-spironolactone derivatives: characterization _in vivo_ and _in vitro_. _J

Pharmacol Exp Ther_ 1987; 240: 650–656. CAS  PubMed  Google Scholar  * Silvestre JS, Heymes C, Oubenaissa A, _et al_: Activation of cardiac aldosterone production in rat myocardial

infarction. Effect of angiotensin II receptor blockade and role in cardiac fibrosis. _Circulation_ 1999; 99: 2694–2701. Article  CAS  Google Scholar  * Katada J, Meguro T, Saito H, _et al_:

Persistent cardiac aldosterone synthesis in angiotensin II type 1A receptor–knockout mice after myocardial infarction. _Circulation_ 2005; 111: 2157–2164. Article  CAS  Google Scholar  *

Funder JW, Pearce PT, Smith R, Smith AI : Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. _Science_ 1988; 242: 986–989. Article  Google Scholar  *

Sheppard KE, Autelitano DJ : 11β-Hydroxysteroid dehydrogenase 1 transforms 11-dehydrocorticosterone into transcriptionally active glucocorticoid in neonatal rat heart. _Endocrinology_ 2002;

143: 198–204. Article  CAS  Google Scholar  * Lombes M, Oblin ME, Gasc JM, Baulieu EE, Farman N, Bonvalet JP : Immunohistochemical and biochemical evidence for a cardiovascular

mineralocorticoid receptor. _Circ Res_ 1992; 71: 503–510. Article  CAS  Google Scholar  * Young M, Fullerton M, Dilley R, Funder J : Mineralocorticoids, hypertension, and cardiac fibrosis.

_J Clin Invest_ 1994; 93: 2578–2583. Article  CAS  Google Scholar  * Sato A, Funder JW : High glucose stimulates aldosterone-induced hypertrophy _via_ type 1 meneralocorticoid receptors in

neonatal rat cardiomyocytes. _Endocrinology_ 1996; 137: 4145–4153. Article  CAS  Google Scholar  * Qin W, Rudolph AE, Bond BR, _et al_: Transgenic model of aldosterone-driven cardiac

hypertrophy and heart failure. _Circ Res_ 2003; 93: 69–76. Article  CAS  Google Scholar  * Nagata K, Obata K, Xu J, _et al_: Mineralocorticoid receptor antagonism attenuates cardiac

hypertrophy and failure in low-aldosterone hypertensive rats. _Hypertension_ 2006; 47: 656–664. Article  CAS  Google Scholar  * Konishi A, Tazawa C, Miki Y, _et al_: The possible roles of

mineralocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 2 in cardiac fibrosis in the spontaneously hypertensive rat. _J Steroid Biochem Mol Biol_ 2003; 85: 439–442. Article  CAS

  Google Scholar  * Castren M, Trapp T, Berninger B, Castren E, Holsboer F : Transcriptional induction of rat mineralocorticoid receptor gene in neurones by corticosteroids. _J Mol

Endocrinol_ 1995; 14: 285–293. Article  CAS  Google Scholar  * Lister K, Autelitano DJ, Jenkins A, Hannan RD, Sheppard KE : Cross talk between corticosteroids and alpha-adrenergic signalling

augments cardiomyocyte hypertrophy: a possible role for SGK1. _Cardiovasc Res_ 2006; 70: 555–565. Article  CAS  Google Scholar  * Sun K, Yang K, Challis JR : Differential regulation of

11β-hydroxysteroid dehydrogenase type 1 and 2 by nitric oxide in cultured human placental trophoblast and chorionic cell preparation. _Endocrinology_ 1997; 138: 4912–4920. Article  CAS 

Google Scholar  * Suzuki S, Tsubochi H, Ishibashi H, _et al_: Inflammatory mediators down-regulate 11β-hydroxysteroid dehydrogenase type 2 in a human lung epithelial cell line BEAS-2B and

the rat lung. _Tohoku J Exp Med_ 2005; 207: 293–301. Article  CAS  Google Scholar  * Fukushima K, Funayama Y, Yonezawa H, _et al_: Aldosterone enhances 11β-hydroxysteroid dehydrogenase type

2 expression in colonic epithelial cells _in vivo_. _Scand J Gastroenterol_ 2005; 40: 850–857. Article  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS *

Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan Mitsuo Takeda, Tetsuya Tatsumi, Shinsaku Matsunaga, Hironori Hayashi, Masaki Kimata, 

Shoken Honsho, Susumu Nishikawa, Akiko Mano, Jun Shiraishi, Hiroyuki Yamada, Tomosaburo Takahashi, Satoaki Matoba & Hiroaki Matsubara * Department of Clinical Pharmacology, Kyoto

Pharmaceutical University, Kyoto, Japan Miyuki Kobara Authors * Mitsuo Takeda View author publications You can also search for this author inPubMed Google Scholar * Tetsuya Tatsumi View

author publications You can also search for this author inPubMed Google Scholar * Shinsaku Matsunaga View author publications You can also search for this author inPubMed Google Scholar *

Hironori Hayashi View author publications You can also search for this author inPubMed Google Scholar * Masaki Kimata View author publications You can also search for this author inPubMed 

Google Scholar * Shoken Honsho View author publications You can also search for this author inPubMed Google Scholar * Susumu Nishikawa View author publications You can also search for this

author inPubMed Google Scholar * Akiko Mano View author publications You can also search for this author inPubMed Google Scholar * Jun Shiraishi View author publications You can also search

for this author inPubMed Google Scholar * Hiroyuki Yamada View author publications You can also search for this author inPubMed Google Scholar * Tomosaburo Takahashi View author publications

You can also search for this author inPubMed Google Scholar * Satoaki Matoba View author publications You can also search for this author inPubMed Google Scholar * Miyuki Kobara View author

publications You can also search for this author inPubMed Google Scholar * Hiroaki Matsubara View author publications You can also search for this author inPubMed Google Scholar

CORRESPONDING AUTHOR Correspondence to Tetsuya Tatsumi. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Takeda, M., Tatsumi, T., Matsunaga, S. _et al._

Spironolactone Modulates Expressions of Cardiac Mineralocorticoid Receptor and 11_β_-Hydroxysteroid Dehydrogenase 2 and Prevents Ventricular Remodeling in Post-Infarct Rat Hearts. _Hypertens

Res_ 30, 427–437 (2007). https://doi.org/10.1291/hypres.30.427 Download citation * Received: 21 April 2006 * Accepted: 20 December 2006 * Issue Date: 01 May 2007 * DOI:

https://doi.org/10.1291/hypres.30.427 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not

currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * aldosterone * apoptosis * heart failure * myocardial

infarction * remodeling