Effects of eplerenone on transcriptional factors and mRNA expression related to cardiac remodelling after myocardial infarction

Soichiro Enomoto ¹, Minoru Yoshiyama ^1*, Takashi Omura ¹, Ryo Matsumoto ¹, Takanori Kusuyama ¹, Shokei Kim ¹, Yasukatsu Izumi ¹, Kaname Akioka ¹, Hiroshi Iwao ¹, Kazuhide Takeuchi ¹ and Junichi Yoshikawa ¹

¹ Osaka City University Medical School, Japan

^* To whom correspondence should be addressed. E-mail: yoshiyama{at}med.osaka-cu.ac.jp.

Accepted 13 January 2005

Abstract

Background: Recent studies have shown that aldosterone blockade reduces morbidity and mortality among patients with severe heart failure. However, little is known about the molecular mechanisms of the effects of aldosterone blockade on cardiac remodelling. Therefore, we examined the effects of eplerenone, a selective aldosterone blocker, on cardiac function after myocardial infarction (MI) and myocardial remodelling related transcriptional factors and mRNA expression in non-infarcted myocardium.

Method and results: MI was induced by ligation of the coronary artery in Wistar rats. Rats were randomly assigned to a vehicle-treated group or an eplerenone-treated group (100mg/kg/day). At four weeks after MI, left ventricular end-diastolic pressure (LVEDP), left ventricular weight (LVW) and left ventricular end-diastolic dimension (LVDd) were increased in MI rats, eplerenone significantly reduced the increase in LVEDP, LVW and LVDd. The MI rats showed the decreased ejection fraction as systolic dysfunction, and the increased E wave/A wave ratio and E deceleration rate as diastolic dysfunction. Eplerenone significantly attenuated this systolic and diastolic dysfunction. Myocardial interstitial fibrosis, transcriptional activities of activator protein-1 and nuclear factor- kappa B and mRNA expression of monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, arterial natriuretic peptide, brain natriuretic peptide, collagen type I and III were significantly increased at 4 weeks after MI. Eplerenone significantly attenuated the interstitial fibrosis and suppressed the transcriptional activity and mRNA expression of these genes.

Conclusions: When administered after MI, eplerenone prevents cardiac remodeling accompanied by systolic and diastolic dysfunction, and inhibits abnormal myocardial transcriptional activities and gene expression.

Keywords: aldosterone, cardiac remodeling, eplerenone, gene expression, myocardial infarction

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