Low-dose
mineralocorticoid receptor antagonists reduce morbidity and mortality in patients with
heart failure and
myocardial infarction, despite normal plasma
aldosterone levels. Since apoptosis plays an important role in
heart failure and postinfarction
left ventricular remodeling, we examined whether low-dose
mineralocorticoid receptor antagonists modulate cardiomyocyte death by regulating the apoptosis repressor
protein apoptosis repressor with caspase recruitment domain to lessen the extent of apoptosis. Hearts from adult male Sprague-Dawley rats were subjected to regional
ischemia followed by reperfusion ex vivo, with
mineralocorticoid receptor antagonists added to perfusates before
ischemia. Low-dose
spironolactone (10 nmol/L) or
eplerenone (100 nmol/L) significantly reduced
infarct size.
Spironolactone also prevented cleavage of the apoptotic
chromatin condensation inducer in the nucleus and of the
inhibitor of caspase-activated DNAse induced by
ischemia-reperfusion, thereby abolishing
chromatin condensation and internucleosomal cleavage.
Ischemia-reperfusion-induced activation of
caspases 2, 3, and 9, but not
caspase 8, was prevented by
spironolactone, suggesting targeted regulation of the intrinsic pathway. Low-dose
spironolactone and
eplerenone prevented loss of the apoptosis repressor with the caspase recruitment domain and reduced myocyte death. In H9c2 cells,
mineralocorticoid receptor activation by
aldosterone resulted in apoptosis repressor with caspase recruitment domain degradation and enhanced apoptosis; these actions were prevented by coadministration of
spironolactone. Using a triple
lysine mutant we identified that
aldosterone enhances posttranscriptional degradation of the apoptosis repressor with a caspase recruitment domain via the
ubiquitin-proteasomal pathway. Our data demonstrate that low-dose
mineralocorticoid receptor antagonists reduce
infarct size and apoptosis in the reperfused myocardium by preventing the apoptosis repressor with caspase recruitment domain degradation.