Glycemic Origins of Endothelial Dysfunction

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PROJECT SUMMARY Obesity has been well-documented as a major risk factor for cardiovascular disease. Our lab has demonstrated that increases in reactive oxygen species (ROS) produced by NADPH Oxidase 1 (NOX1) have been shown to contribute to endothelial dysfunction, a hallmark of obesity-driven cardiovascular disease. Our studies suggest that galectin-3 (GAL-3), an advanced glycation end-product receptor associated with cardiovascular disease, may be a mechanistic link between aberrant glycemic control found in obesity and disruption of metabolism driving vascular disease. Additionally, hypermuscular obese mice have been shown to exhibit greater glycemic control and ameliorated endothelial dysfunction. However, the mechanisms by which GAL-3 drives vascular disease are poorly understood. Therefore, the central hypothesis of this proposal is that GAL-3 is the link between metabolic dysfunction and NOX-1 mediated impairment of endothelial health. This hypothesis will be tested in two specific aims. Aim 1 will test the hypothesis that metabolic dysfunction drives expression of GAL-3 and NOX1. We will assess endothelial expression of GAL-3, NOX1, and attendant co-factors in lean and obese mice, as well as in obese mice with improved metabolism by either myostatin knockout or treatment with metformin or dapagliflozin. Additionally, we will utilize a novel db/db/GAL-3 knockout mouse to asses the role of GAL-3 in mediating expression of NOX 1 and vascular oxidative stress. Aim 2 will test the hypothesis that GAL- 3 is the link between metabolic dysfunction and impaired endothelial function. Utilizing the novel mouse model generated above, we will assess overall metabolic status, as well as endothelial function using pressure myography on resistance microvessels. Finally, in vivo vascular function will be assessed using radiotelemetry to measure arterial pressure and a hind limb ischemia model to investigate recovery of perfusion.This project will allow me to develop new technical skills such as pressure myography and radio telemetry, and will allow me to gain expertise in conducting rigorous, hypothesis-driven research. The project will be conducted under the mentorship of Dr. David Stepp in the Vascular Biology Center at the Medical College of Georgia at Augusta University, which has a rich history of successful pre- and post-doctoral training. The proposed project is for 3 years of funding with the proposed aims divided amongst the 3 years of funding, culminating with a dissertation defense at the end of the third year. We anticipate that findings from this novel proposal will identify injurious overexpression of GAL-3 as a key determinant of NOX1-mediated endothelial dysfunction in obesity-induced metabolic disease and will provide insight into avenues for potential therapeutics to restore oxidative balance and improve cardiovascular health.