Program Director/Principal Investigator (Last, First, Middle): Mohamed, Abeer PROJECT SUMMARY (See instructions): Obesity is a growing global epidemic and healthcare burden. The cardiovascular risk associated with obesity is well-documented, yet specific pathophysiological mechanisms are poorly understood. The broad, long term goal of my currently funded R00 application is to identify valid targets and strategies for the prevention and treatment of obesity-related cardiovascular disease (CVD). The central hypothesis in my R00 application was that tissue hypoxia in obese subjects results in dysfunctional perivascular adipocytes that secrete lots of inflammatory mediators and adversely affect vascular function. Data from my current study demonstrated augmented production of heparinase by adipocytes isolated from obese subjects compared with non-obese controls. Heparinase is an enzyme that degrades the endothelial cell glycocalyx, which is a carbohydrate- rich layer that lines the vascular endothelium and plays a critical role in maintaining several aspects of vascular homeostasis. Accordingly, we propose that the impaired vascular function we observed in the arterioles isolated from obese subjects could be, at least in part, attributed to the induction of adipocyte-derived heparinase and the disruption of endothelial glycosylation. Thus, the primary objective of the present supplemental proposal is to investigate endothelial glycocalyx shedding from the arteriolar surface and its subsequent enrichment in the circulation. In the current R00 project, we study the microvasculature of morbidly obese subjects, which makes us well-poised to employ the CF-GSP glycoscience tools to advance our understanding of disturbed endothelial glycosylation as an integral aspect of obesity-related CVD. Our central hypothesis is that the induced heparinase secretion by the hypoxic, dysfunctional adipose tissues in obese individuals is targeting the heparan sulfate glycosaminoglycans in the endothelial glycocalyx resulting in its degradation and eventually, dysregulation of vascular glycobiology. We will test this hypothesis by pursuing the following specific Supplementary Aim: Test the effectiveness of exercise and surgery- induced weight loss on restoring endothelial glycocalyx integrity and circulating heparan sulfate glycosaminoglycans in morbidly obese individuals.
The current study will improve our mechanistic understanding of the biological underpinning of endothelial dysfunction in obesity. This study may identify circulating heparan sulfate glycosaminoglycans as novel preventive and therapeutic targets for improving vascular function in morbidly obese individuals.
