DEC1 deficiency ameliorates myocardial ischemic injury via the p53-dependent apoptosis pathway

Abstract

Abstract Myocardial infarction (MI) causes myocardial hypoxia and subsequent cardiomyocyte death, leading to inflammatory responses that adversely affect prognosis. Clinical outcomes of MI also exhibit diurnal variation, suggesting involvement of circadian clock genes. Differentiated embryo chondrocytes 1 (DEC1) is a clock gene whose expression is induced by hypoxia and has been implicated in the regulation of apoptosis; however, its role in MI remains unclear. To investigate the function of DEC1 in MI, we established a coronary artery ligation model using wild-type and DEC1-deficient (DEC1 ⁻/⁻ ) mice. To assess the contribution of apoptosis, pifithrin-α, a p53-dependent apoptosis inhibitor, was administered following MI induction. DEC1 ⁻/⁻ mice showed increased p53 expression and enhanced apoptosis in the infarcted myocardium. Despite increased apoptotic cell death, inflammatory cell infiltration was significantly reduced, and overall survival after MI was improved compared with wild-type mice. Administration of pifithrin-α to DEC1 ⁻/⁻ mice attenuated apoptosis and abolished the survival benefit. Additionally, expression of survivin, an inhibitor of apoptosis protein, was downregulated in DEC1 ⁻/⁻ hearts after MI. These findings indicate that DEC1 deficiency modulates MI outcomes by enhancing p53-dependent apoptosis while suppressing post-infarction inflammatory responses. DEC1 may therefore represent a novel regulatory factor linking hypoxia, circadian signaling, and myocardial injury.