PROJECT SUMMARY It is well known that obesity drives cardiovascular disease, but the mechanisms involved are incompletely understood and interventions that break the links between weight gain and vascular disease remain a critical barrier to treatment. Upregulation of NOX1-derived oxidants is a key mechanism of endothelial dysfunction in obesity but the factors precipitating this impairment are unknown. A fundamental concept in cardiovascular physiology is that blood flow is regulated to service metabolism and when metabolism is deranged in obesity, this relationship breaks down and cardiovascular function falters. A major link between cardiovascular function and metabolic demand is the circadian clock, a transcriptional network that regulates daily metabolic rhythms and programs cardiovascular gene expression to anticipate these changes. Genetic disruption of the clock in mice results in endothelial dysfunction and disruptive circadian lifestyles in humans leads to a higher incidence of cardiovascular disease. How the vascular clock becomes disrupted and the subsequent ontology of disease are unknown and resolving these critical deficits in our understanding is the focus of this application. New data from our laboratories have identified extensive circadian disruption in the db/db mouse, which exhibits profound obesity and NOX1-mediated endothelial dysfunction. Breeding these mice to a per luc reporter mouse revealed near abrogation of circadian rhythms in the aorta along with an 80% reduction in cyclic gene expression and diminished expression of clock regulated genes. Subsequent studies identified exaggerated hyperglycemia as a potential circadian disruptor and Galectin-3 and Cezanne as novel mechanisms that may influence NOX1 ? eNOS balance to promote vascular dysfunction. Based on these observations, the core hypothesis of this proposal is that obesity causes vascular disease secondary to loss of function of the vascular circadian clock. We will test hypothesis in vivo in novel animal models of obesity with manipulated components of circadian control and in vitro to identify new cellular mechanisms that may be targets for the treatment of vascular disease in obesity.
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