Abstract 463: Circadian Clock Disruption Promotes Cardiac Cell Death During Hypoxic Injury

Abstract

Circadian rhythms play a fundamental role in cell metabolism and tissue homeostasis as well as in the diurnal oscillation of physiological processes such as blood pressure. Zeitgebers influence the circadian rhythms by serving as molecular switches for re-setting the intrinsic cellular clock. Herein, we show that oxygen is a Zeitgeber 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 mitochondrial clearance and autophagy. Cardiac myocytes exhibited phasic oscillations in clock gene expression under basal conditions which was disrupted during hypoxia. This was accompanied by a marked time dependent decline in clock gene transcription that was maximal at ZT+18 and coincided with a reciprocal increase in mitochondrial clearance. Loss of function mutations of clock that disrupted nuclear localization or DNA binding to BMAL-1 promoted wide-spread cell death. Hence, the findings of the present study provide a novel signaling axis that operationally links hypoxia regulated clock gene expression and mitochondrial turn-over to cell survival.