Published Online
on February 25, 2008

A more recent version of this article appeared on April 1, 2008

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Submitted on September 4, 2007
Revised on September 25, 2007

Immediate Mineralocorticoid Receptor Blockade Improves Myocardial Infarct Healing by Modulation of the Inflammatory Response

Daniela Fraccarollo; Paolo Galuppo; Susanne Schraut; Susanne Kneitz; Nico van Rooijen; Georg Ertl; and Johann Bauersachs^*

From the Medizinische Klinik und Poliklinik I (D.F., P.G., S.S., G.E., J.B.), Institut fuer Virologie and Immunbiologie (S.K.), Julius-Maximilians-Universität Würzburg, Würzburg, Germany; Department of Cell Biology (N.v.R.), Free University, Amsterdam, the Netherlands.

^* To whom correspondence should be addressed. E-mail: j.bauersachs{at}medizin.uni-wuerzburg.de.

Abstract—Mineralocorticoid receptor (MR) blockade reduces morbidity and mortality after acute myocardial infarction; however, the underlying mechanisms are still under investigation. This study examined whether MR antagonism promotes healing of the infarcted myocardium. Starting immediately after coronary ligation, male Wistar rats were treated with the selective MR antagonist eplerenone (100 mg/kg per day by gavage) or placebo for 2 to 7 days. At 7 days, eplerenone therapy versus placebo significantly reduced thinning and dilatation of the infarcted wall, improved left ventricular function, and enhanced neovessel formation in the injured myocardium. At 2 days, eplerenone-treated rats displayed lower plasma corticosterone levels, higher circulating blood monocytes, and more macrophages infiltrating the infarcted myocardium. MR blockade led to a transient upregulation (at days 2 and 3 but not at day 7) of monocyte chemoattractant protein-1, tumor necrosis factor-, interleukin-1, interleukin-6, interleukin-10, and interleukin-4 and an increase in factor XIIIa protein expression in the healing myocardium. Prevention of macrophage accumulation into the infarct zone by treatment with liposome-encapsulated clodronate almost abrogated the protein expression of factor XIIIa and the beneficial effects of eplerenone on infarct expansion. In conclusion, selective MR blockade immediately after myocardial infarction accelerated macrophage infiltration and transiently increased the expression of healing promoting cytokines and factor XIIIa in the injured myocardium resulting in enhanced infarct neovascularization and reduced early LV dilation and dysfunction.

Key words: aldosterone • healing • inflammation • myocardial infarction • heart failure

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