Low-dose spironolactone prevents apoptosis repressor with caspase recruitment domain degradation during myocardial infarction

Thi Yen Loan Le, Mahidi Mardini, Viive M. Howell, John W. Funder, Anthony W. Ashton, Anastasia S. Mihailidou*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1164-1169
Number of pages6
JournalHypertension
Volume59
Issue number6
DOIs
Publication statusPublished - Jun 2012
Externally publishedYes

Keywords

  • Apoptosis
  • Cardiovascular disease
  • Heart failure
  • Ischemia
  • Myocardial infarction
  • Reperfusion injury

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