The Roles of Circadian Disruption and Reactive Oxygen Species Overproduction in the Development of Obesity-Associated Cardiovascular Disease

Abstract

Obesity is a complex and multifactorial disease that is endemic in the United States, affecting over 40% of the US population and contributing to over $150 billion in medical cost. Obesity and metabolic disease are major risk factors for cardiovascular disease, which is the leading cause of death among Americans, especially those in the southeast. While the detrimental effects of obesity on cardiovascular health are well-documented, the mechanisms linking aberrant metabolism to vascular dysfunction are poorly understood. In the present study, we investigate the role of the vascular endothelium in mediating the progression of cardiometabolic disease through disruption of the peripheral circadian clock as well as through overproduction of reactive oxygen species, both of which are implicated in the development of endothelial dysfunction and the downstream acute cardiovascular diseases it predicts. We demonstrate that obesity causes a unique circadian disruption in the endothelium that is not recapitulated by other established models of circadian disruption, and that rhythmic expression of the essential vasodilatory enzyme endothelial nitric oxide synthase (eNOS) is disturbed. Expression of NADPH oxidase I (NOX1), the major pathological reactive oxygen species (ROS)-producing enzyme in the vasculature, was markedly increased in the endothelium, and was found to be even more highly expressed in the obese microvascular endothelium. Further, endothelial expression of the receptor for glycation end-products galectin-3 (GAL3) was found to correlate with NOX1 expression levels, leading us to hypothesize that GAL3 contributes to obesity-induced NOX1 overexpression in the microvascular endothelium. We demonstrate that deletion of GAL3 resolves obesity-induced endothelial dysfunction and hypertension by decreasing NOX1 expression and subsequent ROS overproduction. Finally, we demonstrate that the GAL3/NOX1 axis is amenable to beneficial changes in glucose handling by treatment with metformin, augmentation of skeletal muscle mass, or improvement of insulin signaling. Taken together, these data indicate that GAL3 is an attractive therapeutic target to ameliorate obesity-induced cardiovascular disease.