Research Project
10271703
Obesity is an overwhelming epidemic and healthcare burden. The cardiovascular risk associated with obesity is well-documented, yet specific pathophysiological mechanisms are poorly understood. The broad, long term objective of this application is to define mechanisms driving obesity-induced cardiovascular dysfunction. Obesity causes endothelial dysfunction in visceral adipose arteries (VAA) whereas subcutaneous adipose arteries (SAA) remain functional. This dichotomy in vascular function presents a unique opportunity to identify novel, vascular bed-specific targets in combatting cardiovascular disease in obesity. A hallmark of endothelial dysfunction is reduced dilations to increased blood flow. We recently identified flow- activated Kir2.1 channels as critical regulators of flow-induced vasodilation. Furthermore, our preliminary evidence reveals that reduced dilations to flow in VAA of obese mice and humans is through inhibition of endothelial Kir2.1, whereas SAA Kir2.1 function is intact. This implicates Kir2.1 as a novel, vascular bed-specific target. The goal of the present study is to determine the mechanisms of obesity-induced endothelial dysfunction that result in the loss of Kir function specifically in VAA. We show that Kir2.1 inhibition is dependent on the presence of CD36, a scavenger receptor that is upregulated in obesity. CD36 contributes to the cellular uptake of fatty acids, derivatives of which are well-known to inhibit Kir2.1. We will determine the role of CD36 in inhibiting Kir2.1 in VAA of obese mice and humans. Our hypothesis is that elevated CD36 results in increased fatty acid uptake into endothelial cells which leads to the inhibition of Kir2.1 and endothelial dysfunction. We propose that the underlying impairment of VAA lies in the obesity-induced increase in the expression and function of CD36 in mice and humans and results in Kir2.1 inhibition in VAA, effects that do not occur in SAA with obesity. The proposed studies, as part of the NIH COBRE Phase 2, will provide the foundation for the applicant's procurement of an NIH R01. The major project milestone is to produce adequate preliminary data by the completion of this project to support a competetive R01 proposal. The main career goal of the applicant is to establish a successful, externally funded research program using gold standard approaches to identify new targets in cardiovascular disease. The University of Delaware provides a resource rich environment befitting of a productive research position.
