Abstract 488: Clock Regulates Autophagy and Cell Survival of Cardiac Myocytes During Hypoxia Stress

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 autophagy. 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 mitochondrial autophagy genes including beclin-1 . Loss of function mutations of clock that disrupted nuclear localization or DNA binding promoted wide-spread cell death. Hence, the findings of the present study provide the first direct evidence that hypoxia is a Zeitgeber for regulating Clock gene expression and cell survival of cardiac myocytes during hypoxic injury.