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

Abstract

Objective: To examine 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.

Methods: 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 (100 mg/kg/day).

Results: At four weeks after MI, left ventricular (LV) end diastolic pressure, LV weight, and LV end diastolic dimension were increased in MI rats. Eplerenone significantly reduced the increase in LV end diastolic pressure, LV weight, and LV end diastolic dimension. In the MI rats the decreased ejection fraction indicated systolic dysfunction and the increased E wave to A wave ratio and E deceleration rate indicated diastolic dysfunction. Eplerenone significantly attenuated this systolic and diastolic dysfunction. Myocardial interstitial fibrosis, transcriptional activities of activator protein 1 and nuclear factor kappaB, and mRNA expression of monocyte chemoattractant protein 1, plasminogen activator inhibitor 1, atrial natriuretic peptide, brain natriuretic peptide, and collagen types I and III were significantly increased at four weeks after MI. Eplerenone significantly attenuated interstitial fibrosis and suppressed transcriptional activity and mRNA expression of these genes.

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

Figure 1

Histopathological analysis of the non-infarcted myocardium of rat left ventricle. Photomicrographs show sirius red stained cardiac sections from sham operated rats (Sham), infarcted rats treated with vehicle (Vehicle), and infarcted rats treated with eplerenone (Ep) (n  =  6 in each group). Bar graphs show fraction of interstitial fibrosis and myocyte cross sectional area (MCSA). *p < 0.05 v sham; **p < 0.01 v sham; ††p < 0.01 v vehicle. Values are mean (SEM).

Figure 2

Effects of eplerenone on non-infarcted myocardial activator protein 1 (AP-1) and nuclear factor (NF) κB DNA binding activities at four weeks after myocardial infarction. Myocardial AP-1 and NF-κB DNA binding activities were compared in sham operated rats (n  =  8), infarcted rats treated with vehicle (n  =  9), and infarcted rats treated with Ep (n  =  9). The upper panels show representative autoradiographs of gel mobility shift assay of AP-1 and NF-κB DNA binding activities. Each bar represents mean (SEM) (n  =  6). *p < 0.05 v sham; **p < 0.01 v sham; †p < 0.05 v vehicle.

Figure 3

(A) Effects of eplerenone on non-infarcted myocardial mRNA expression at four weeks after myocardial infarction (n  =  6 in each group). Myocardial mRNA expression of plasminogen activator inhibitor 1 (PAI-1) and monocyte chemoattractant protein 1 (MCP-1) were compared in sham operated rats, infarcted rats treated with vehicle, and infarcted rats treated with Ep. Each panel shows a representative autoradiogram of northern blot analysis of PAI-1 and MCP-1. **p < 0.01 v sham; †p < 0.05 v vehicle. Values are mean (SEM). (B) Immunohistochemical staining for MCP-1 antigen in the non-infarcted myocardium. Arrows denote positive staining for MCP-1.