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

Abstract

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.

Remodeling in the ischemic heart: the stepwise progression for heart

“…Mill et al (17) showed that aldosterone also contributes to increased collagen deposition in non-infarcted viable tissue. Another effect of aldosterone observed in infarcted rats showed that immediate treatment with eplerenone, a selective aldosterone antagonist, improved left ventricular function and reduced deleterious effects of cardiac remodeling by modulation of inflammatory response in acute phase of the healing process (36). This was mediated by acceleration of macrophage infiltration and necrotic re-absorption.…”

Mineralocorticoid Receptor Activation and Mineralocorticoid Receptor Antagonist Treatment in Cardiac and Renal Diseases

“…29 Increased oxidative stress, inflammation, and fibrosis are evident in several animal models of cardiac and renal diseases (eg, rats post-MI, dogs with HF, and uninephrectomized diabetic rats). 18,[38][39][40] Furthermore, MR activation stimulates apoptosis and causes vasoconstriction and reduced blood flow in the animal heart and kidneys. 8,18,41,42 Reduced endothelium-dependent vasodilatation is thought to be caused by an aldosterone-mediated decrease in the bioavailability of nitric oxide.…”

Deletion of Cardiomyocyte Mineralocorticoid Receptor Ameliorates Adverse Remodeling After Myocardial Infarction

“…[1][2][3][4] However, it remains unclear whether the cardioprotective effects of MR antagonists can be attributed to inhibition of the cardiomyocyte MR. While attenuation of left ventricular (LV) dilation and excessive extracellular matrix turnover [5][6][7][8][9] and prevention of electric remodeling appear to be essential mechanisms of MR antagonism, 10,11 extracardiac effects such as renal sodium excretion and potassium sparing, restoration of autonomic balance, and improvement in vascular endothelial dysfunction may be of particular importance. 9,[12][13][14] …”