Immediate mineralocorticoid receptor blockade improves myocardial infarct healing by modulation of the inflammatory response.

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-alpha, interleukin-1beta, 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.

• Authors: Daniela Fraccarollo, Paolo Galuppo, Susanne Schraut, Susanne Kneitz, Nico van Rooijen, Georg Ertl, Johann Bauersachs
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 51 Issue 4 Pg. 905-14 (Apr 2008) ISSN: 1524-4563 [Electronic] United States
• PMID: 18299485 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Mineralocorticoid Receptor Antagonists
• RNA, Messenger
• Clodronic Acid
• Spironolactone
• Aldosterone
• Eplerenone
• Collagen
• Factor XIIIa

Topics

• Aldosterone (blood)
• Animals
• Clodronic Acid (pharmacology)
• Collagen (metabolism)
• Cytokines (metabolism)
• Eplerenone
• Factor XIIIa (genetics)
• Heart Failure (drug therapy, immunology, pathology)
• Humans
• Male
• Mineralocorticoid Receptor Antagonists (pharmacology)
• Monocytes (drug effects, immunology, metabolism)
• Myocardial Infarction (drug therapy, immunology, pathology)
• Myocarditis (drug therapy, pathology)
• Myocardium (metabolism, pathology)
• Neovascularization, Physiologic (drug effects)
• RNA, Messenger (metabolism)
• Rats
• Rats, Wistar
• Spironolactone (analogs & derivatives, pharmacology)
• Ventricular Function, Left (drug effects)
• Wound Healing (drug effects)