All ETDs from UAB

Advisory Committee Chair

Martin E Young

Advisory Committee Members

Molly Bray

John Chatham

Lori L McMahon

Qinglin Yang

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

It is well established that multiple parameters of cardiovascular physiology and pathophysiology exhibit diurnal variations. For example, human heart rate and blood pressure peak during the morning and trough in the evening. Similarly, there is a morning prevalence for the onset of multiple adverse cardiovascular events, including myocardial ischemia, arrhythmias, and sudden cardiac death. Traditionally these rhythms have been attributed to rhythms in neurohumoral stimulation. However recent identification of the circadian clock mechanism in cardiovascular relevant cell types, including the cardiomyocyte, has prompted investigation into its role in modulating myocardial physiology and pathophysiology over the course of the day. Preliminary studies demonstrate that the cardiomyocyte circadian clock plays an important role in regulating numerous aspects of myocardial physiology, including gene expression, fatty acid metabolism, and contractile function. Therefore, the first aim of this thesis was to investigate a novel role for the cardiomyocyte circadian clock in glucose metabolism. We demonstrate that the heart exhibits time-of-day-dependent oscillations in oxidative and non-oxidative glucose metabolism. Additionally, these rhythms appear to be secondary to cardiomyocyte circadian clock regulation of glucose uptake. Disruption of the circadian clock has been described in multiple animal models of cardiovascular disease including diabetes mellitus, aging, pressure overload-induced cardiac hypertrophy, and ischemia/reperfusion. However, the role of the cardiomyocyte circadian clock in the responsiveness of the myocardium to these stresses is unknown. The second aim of this thesis was to examine whether disruption of the cardiomyocyte circadian clock alters responsiveness of the heart to various stresses associated with cardiovascular disease. We demonstrate that genetic disruption of the circadian clock does not alter myocardial adaptation/maladaptation to aging or simulated shift work. However, we expose a role for the cardiomyocyte circadian clock in regulating a diurnal variation in the hearts responsiveness to pro-hypertrophic stimuli. Additionally, we describe a profound oscillation in the hearts tolerance to ischemia/reperfusion which is regulated by the cardiomyocyte circadian clock. These findings expose novel roles for the cardiomyocyte circadian clock in myocardial physiology and pathophysiology. Therefore, it is important to consider the potential contribution that dyssynchrony of the cardiomyocyte circadian clock may play in the pathogenesis of cardiovascular disease.

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