Spironolactone modulates expressions of cardiac mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase 2 and prevents ventricular remodeling in post-infarct rat hearts.
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 ventricular [LV] diastolic dimension [LVDd], fractional shortening [%FS]), hemodynamic parameters (LV systolic pressure [LVSP], LV end-diastolic pressure [LVEDP], dP/dt(max) and dP/dt(min)) and collagen accumulation quantitated by Masson's Trichrome staining were significantly improved in the spironolactone-treated MI group on the 14th day, compared with the 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 11beta-hydroxysteroid dehydrogenase 2 (11beta-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 11beta-HSD2, which are enhanced in the remodeling heart.
Takeda
Mitsuo
M
Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan.
Tatsumi
Tetsuya
T
Matsunaga
Shinsaku
S
Hayashi
Hironori
H
Kimata
Masaki
M
Honsho
Shoken
S
Nishikawa
Susumu
S
Mano
Akiko
A
Shiraishi
Jun
J
Yamada
Hiroyuki
H
Takahashi
Tomosaburo
T
Matoba
Satoaki
S
Kobara
Miyuki
M
Matsubara
Hiroaki
H
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013148:Spironolactone / Q000494:pharmacology*; D015996:Survival Rate; D020257:Ventricular Remodeling / Q000187:drug effects*
D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2