Sorbs2 targeting and BK channel regulation in the coronary arteries of patients with type 1 diabetes

Cardiovascular diseases (CVD) are the leading cause of death in both type 1 diabetes (T1D) and type 2 diabetes (T2D). Clinical evidence suggested that the poor clinical outcome of cardiovascular events in diabetic patients are associated with atherosclerosis, vascular inflammation, endothelial dysfunction, and structural remodeling, which lead to coronary vasculopathy and myocardial ischemia.Coronary arterial BK channels, composed of four pore-forming subunits (BK-a) and four regulatory subunits (BK-b1), are the key ionic determinant of vascular tone and play an important role in regulating coronary circulation and myocardial perfusion.However, coronary BK channel function is diminished in diabetes. Over the last 15 years, we have made several important contributions to improve our understanding on BK channelopathy in diabetes. However, most of our knowledge regarding vascular BK channelopathy in diabetes is obtained from animal studies and most of studies were focused on the BK-b1 dysregulation in diabetes. Unlike patients with T2D who have reduced BK-a and BK-b1 protein expression in the coronary arteries, only BK-a protein levels are remarkedly decreased in the coronary arteries of T1D patients. However, the role of BK channels in the coronary artery pathophysiology of human T1D has not been established, and the mechanisms underlying the downregulation of BK-a expression in coronary SMCs of T1D patients is unclear. The Sorbin and SH3 domain-containing protein 2 (Sorbs2), a scaffolding protein, is highly expressed in coronary SMCs. Little is known about the role of Sorbs2 in diabetic coronary vasculopathy. We have exciting preliminary results showing that Sorbs2 physically interacts with BK-a and BK-b1 proteins and regulates BK-a and BK-b1 expression in coronary arterial SMCs. Interestingly, Sorbs2 knockout mice exhibit many common features of diabetic coronary BK channelopathy, albeit these animals have normal body weights and blood glucose levels, indicating that Sorbs2 deficiency is an independent risk factor of BK channel pathology. Most importantly, the protein levels of Sorbs2 are markedly decreased with diminished BK channel-mediated coronary vasodilation in T1D patients. These observations led us to formulate the novel hypothesis that Sorbs2 binds BK channel to form a Sorbs2-BK channel microdomain organization, thereby regulating BK-a and BK-b1 membrane expression and BK channel function in coronary SMCs.