Role of the Molecular Circadian Clock within the Heart

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DESCRIPTION (provided by applicant): The rat heart possesses a fully functional circadian clock. Circadian clocks are intrinsically maintained by molecular mechanisms that condition the cell to changes in its environment. These circadian clocks therefore confer a selective advantage by providing a mechanism for anticipation of change. It is not known, however, which environmental stimuli the circadian clock within the heart anticipates. Diurnal variations in cardiovascular parameters (such as blood pressure, heart rate, and cardiac output) as well as the onset of cardiovascular disease have previously been attributed to neurohumoral factors (e.g. sympathetic activity). In contrast, the second component of stimulus-response coupling, namely the sensitivity of the system to the stimulus, has been largely ignored. The broad objective of this proposal is therefore to test the hypothesis that the circadian clock within the heart synchronizes responsiveness of the heart to diurnal variations in its environmental stimuli, and that impairment of this mechanism results in an inability of the heart to respond appropriately to the onset of such stimuli (i.e. maladaptation). The first specific aim will investigate the potential physiological role(s) of the circadian clock within the heart. Initially we will fully characterize the circadian clock within the heart, utilizing isolated adult rat cardiomyocytes. Next, we will address the nature of the environmental stimuli that the circadian clock allows the heart to anticipate. We intend to investigate whether the rat heart anticipates diurnal variations in substrate availability, workload and/or the energy supply/demand ratio. The second specific aim will address the consequences of impairment of the circadian clock within the heart of rodents due to pressure overload-induced hypertrophy, manipulation of the light/dark cycle, and the generation of a transgenic mouse model with a heart-specific abolition of the circadian clock. Such studies will allow identification of circadian clock-regulated genes in the heart, elucidation of circadian clock-regulated processes in the heart, as well as determination of the consequences of circadian clock impairment on cardiac function. Whether the circadian clock is altered in the failing human heart will also be investigated. Our long-term goals are to establish the molecular mechanisms and physiological role(s) of the circadian clock within the heart, and to determine the pathophysiological consequences of impairment of this mechanism.