Role of mineralocorticoid receptor regulation during experimental myocardial infarction

Abstract

Ischaemic heart disease remains the leading cause of death worldwide. Following an ischaemic event, the primary strategy is to restore blood flow (reperfusion). However, this triggers release of reactive oxygen species, activation of stress-related gene transcription, autophagy and cell death processes leading to further injury (reperfusion injury). Elevated plasma aldosterone levels produce adverse cardiac effects, while mineralocorticoid receptor (MR) antagonists (spironolactone or eplerenone) reduce mortality, although mechanisms have not been defined. The aim of this thesis was to determine the role of MR regulation during experimental myocardial infarction (MI). This was achieved by using an ex-vivo isolated rat heart model and occluding a branch of the left coronary artery (30min) followed by reperfusion (150min). Increased levels of oxidative stress with activated autophagy and apoptosis confirmed our model of MI. Since there are sex differences in cardiac damage during MI, our studies show that androgens downregulate anti-apoptotic protein Bcl-xL, which shifts the balance towards apoptosis leading to aggravated cardiac damage in males compared to females. Expression levels of MR have been reported to be upregulated during MI in males, which could contribute to the aggravated damage, we did not find any significant change in MR expression between male and female rats and hence male rats were used for subsequent studies. Activation of MR by aldosterone (10 nM) increased cardiomyocyte apoptosis and aggravated infarct size during MI; prevented by low-dose MR antagonists. Low-dose (10 nM) spironolactone alone maintained redox balance, prevented activation of stress-related gene transcription and degradation of anti-apoptotic protein ARC, which prevented initiation of apoptosis. These studies provide direct evidence that MR activation aggravates cardiac damage during MI and provide mechanisms for the cardioprotective action of low-dose MR antagonists clinically.