Abstract 20933: Regulation of Hypoxia Induced Cardiac Cell Death by the Intrinsic Circadian Clock

Abstract

Circadian rhythms play a fundamental role in cell metabolism and tissue homeostasis and are influenced by the diurnal oscillation of cellular circadian clock genes. Zeitgebers influence the activation of the circadian rhythm by serving as molecular switches for the intrinsic cellular clock. Herein, we provide new evidence that hypoxia is a Zietgeber for the circadian rhythm and regulator of clock gene expression in cardiac myocytes. We further show that clock gene regulation promotes survival of cardiac myocytes by a mechanism that bi-directionally influences the inducible death protein Bnip3. Cardiac myocytes exhibited phasic oscillations in clock gene expression under basal conditions. Interestingly, in contrast to control cells, a marked time dependent decline in clock gene transcription was observed in cardiac myocytes subjected to hypoxia with maximal decline occurring at 18hrs. This coincided with a reciprocal increase in the expression of the mitochondrial autophagy protein Bnip3 and cell death. Given that Bnip3 is transcriptionally repressed under basal conditions, we reasoned that clock may promote cell survival by negatively regulating Bnip3 gene transcription. While Bnip3 transcription was markedly increased in cardiac myocytes subjected to hypoxia, gain of function of clock suppressed Bnip3 gene activation and cell death of cardiac myocytes. Hence, the findings of the present study provide the first direct evidence that hypoxia is a circadian Zeitgeber for circadian rhythm in cardiac myocytes. We further show that circadian protein Clock regulates cell survival during hypoxic injury by a mechanism that involves the transcriptional repression of Bnip3.