Repair of Vascular Contractility and Mitochondrial Function by NOS Recoupling

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Diabetes (DM) is prevalent in the Veteran community, and there is an excess risk of cardiovascular disease (CVD) in those suffering from this disease. Early signs of CVD pathology include disruptions in vascular cells, making the vasculature a prime target for novel therapeutics. Hormesis, or the ability of cells to adapt and self- regulate when exposed to stress, is disrupted in the vasculature of those with DM. A central lynchpin of homeostasis modulation is the enzyme nitric oxide synthase (NOS). NOS regulates vascular contractility through the production of nitric oxide (NO) and also modulates mitochondrial function. We have shown that the impaired vascular function in animal models of DM is correlated to NOS dysfunction and altered mitochondrial substrate metabolism, function, and dynamics. It is unknown whether restoration of mitochondrial substrate metabolism would repair NOS activity, cellular and mitochondrial function, redox processes, and/or vascular function in those with DM. We hypothesize that disrupted cellular homeostasis intrinsic to the DM vasculature can be restored by reestablishing physiological NOS regulation and mitochondrial fuel metabolism. Many bioactive plant compounds are a platform for commonly used pharmaceuticals and have myriad physiological effects. The flavonoid compound -(-) epicatechin has been shown to induce vasodilation through the direct modulation of NOS; in previous studies, this compound also attenuated excess ROS and improved mitochondrial function. To test our hypothesis, we will treat animal models of DM with the plant compound -(-) epicatechin and measure NOS activity, mitochondrial function and substrate utilization, and vascular contractility. In vitro experiments in endothelial cells treated with -(-) epicatechin will determine the upstream cellular regulation of our functional endpoints. Secondly, we will test the cellular regulation of antioxidant defense in endothelial cells treated with -(-) epicatechin and ascertain any effects on cellular signaling pathways. Ultimately, we will investigate whether the cells' innate homeostatic regulation will be restored by repairing NOS activity with this plant compound. As this natural product is available in food and as a supplement, it may be a candidate for immediate therapeutic use for Veterans suffering from DM and CVD.