The Daily Bulletin

Please join the Chemistry and Physics departments for the seminar "Use of Small Endopeptides to Modulate Cardiovascular Inflammation and Fibrosis," presented by Umesh Sharma, assistant professor in the University at Buffalo's Jacobs School of Medicine and Biomedical Sciences, on Thursday, October 17, from 12:15 to 1:30 p.m. in Technology Building 160.

Abstract
Coronary microvascular disease (CMD) and heart failure are major sequelae of chest radiotherapy in cancer survivors. Large epicardial conduit arteries can be revascularized by stent placement; however, there are no effective therapies currently available to target microvascular disease. Our research aims to investigate the novel and previously unaddressed effects and mechanisms of a small tetrapeptide, N-acetyl-ser-asp-lys-pro (Ac-SDKP), to counteract ionizing radiation (IR)-induced coronary microvascular injury, fibrosis, and cardiac functional impairment.

Our recent studies have demonstrated profound endothelial cell loss and obliterative fibrosis of the small coronary vasculature after radiation exposure. Importantly, administration of Ac-SDKP, a thymosin β4-derived endogenous peptide, not only prevented the cardiac fibro-inflammatory response, but also reconstituted endothelial tight junction proteins (TJPs), which are essential for endothelial barrier integrity. Ac-SDKP was shown to inhibit inflammation and fibrosis in various animal models of cardiovascular remodeling, and our initial data are strongly indicative of the cardioprotective potential of Ac-SDKP. However, the driver mechanisms of coronary microvascular disease and implications of Ac-SDKP therapy in relation to endothelial damage, myocardial perfusion and cardiac function have not been explored. In addition, translational studies for the therapeutic application of Ac-SDKP have been challenging due to its short half-life (T1/2 of 4.5 mins) in serum. Therefore, we have developed a stable, liposomal Ac-SDKP (Lip-Ac-SDKP) formulation, which we intend to test for sustained systemic effects. Currently we are testing  the biological effects of liposome-stabilized Ac-SDKP in regulating endothelial barrier function, leukocyte trafficking, inflammation, and fibrosis. Since Ac-SDKP is known to be stabilized in serum by angiotensin converting enzyme inhibitors (ACEI), synergistic cardioprotective effects of Ac-SDKP together with captopril (an ACEI) are also being examined. We use innovative in vitro models, clinically relevant animal models, and advanced MRI technology to address our aims. We believe that pre-clinical data on the protective effects of stabilized Ac-SDKP against IR-induced coronary microvascular disease will facilitate further translational studies with important therapeutic implications for cancer survivors treated with chest irradiation.