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Diabetes mellitus has become an epidemic in the United States with about 29.1 million people diagnosed with diabetes and another 86 million with prediabetes. A large body of evidence indicates that diabetes is an independent risk of cardiovascular diseases which are the leading cause of death in both men and women with diabetes. Since the last decade, I have dedicated my career to better understanding of vascular smooth muscle pathology that leads to cardiovascular complications in diabetes. Specifically, it is of great interest and immense pleasure to work on the molecular mechanisms leading to the large conductance Ca2+-activated K+ (BK) channel dysfunction in coronary smooth muscle myocytes, and to determine the BK channels as potential molecular targets for the treatment of vascular complications in diabetes. Our program employs the state-of-the-art patch clamp techniques and conventional intracellular recordings, coupled with cutting-edge cellular, biochemical and molecular technologies to study vascular ion channel functions. We have made several important contributions demonstrating the critical role of oxidative stress on BK channelopathy and coronary vasculopathy in both type 1 and type 2 diabetes. Specifically, we have discovered that the impaired BK channel α subunit (BK-α) activity by glucotoxicity is due to a redox-mediated protein modification at a specific cysteine residue in BK-α, while diminished BK channel beta 1 subunit (BK-b1) function in diabetic vessels is resulted from an increase of ubiquitin/proteasome-dependent BK-b1 protein degradation. Moreover, we have identified two E3 ligases, antrogin-1 and the muscle ring finger protein-1 (MuRF1) which specifically target BK-b1 proteins and facilitate the protein degradation in diabetic vessels. Most importantly, increase of BK channel protein expressions and BK preserves BK channel function and BK channel-mediated coronary vasoreactivity in diabetic mice, indicating that BK channels are the potential target for the treatment of diabetic vascular complications in animal models. However, whether BK channel pathology observed from animal studies will be correctly interpreted and applied to human subjects with diabetes is unknown. Our current project is to determine the molecular mechanisms underlying the regulation of BK-α and BK-b1 expression by the nuclear factor erythroid-2-related factor 2 (Nrf2) signaling in the coronary microvessels of type 2 diabetic patients and to further investigate the therapeutic potential of Nrf2-BK channel targeting in the treatment of diabetic cardiovascular complications. I have successfully carried out my own research projects founded by American Diabetes Association and American Heart Association, as well as by Mayo Clinic and Mayo Foundation. The short-term goals of my research are to delineate the pathophysiologic roles of BK channels in coronary dysfunction in human subjects with diabetes, and to establish BK channels as therapeutic targets for diabetic patients with cardiovascular diseases. My long-term goals are to develop new modalities of clinical therapy and to improve the life quality of patients with diabetes mellitus.
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Circulation researchno. 7 (2024): 858-871
NEUROLOGYno. 23 (2022): S13-S13
Journal of Nanjing Medicial Universityno. 2 (2022)
Circulationno. Suppl_1 (2022)
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