Amy Keller, P.h.D.
Dates of funding: 2014-2017
Assistant Professor, Division of Endocrinology, Metabolism, & Diabetes, University of Colorado School of Medicine
In people with diabetes (DM), cardiovascular disease, (CVD) is a major cause of death; this is not alleviated by CVD management or standard treatments for DM. Vascular contractility and mitochondria dysfunction are not only associated with hyperglycemia, decreased antioxidant defense, and insulin resistance, but precede vascular inflammation, vascular stiffness, and smooth muscle cell (SMC) apoptosis. As we and others have shown that nitric oxide synthase (NOS) enzymes regulate contractility and mitochondrial function, targeting NOS recoupling is a potential strategy for novel vasculature therapeutics in DM. Sepiapterin, a NOS coupler, has been shown to restore NOS function both in vivo and in vitro. Our findings in vivo with sepiapterin supplementation include an unexpected beneficial effect on blood glucose. This compound also significantly normalized both vascular contractility and mitochondrial function. This proof-of-concept study provided a platform for the research of other potentially bioactive and multifactorial compounds, sourced from medicinal plants, as homeostasis regulators in the diabetic vasculature. To date, we have continued our in vivo and in vitro studies begun in our pilot award, and broadened our investigation of other in vivo function and cellular mechanisms of action. (-)-epicatechin (EPICAT), a compound found in food and known to modulate NOS activity is central to our current work, and we and others have shown that it restores vascular relaxation and modulates mitochondrial activity. Overall, our research continues to investigate whether disrupted cellular homeostasis intrinsic to the DM vasculature can be restored by reestablishing physiological NOS regulation and mitochondrial fuel metabolism.