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

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Project Summary Type 1 diabetes (T1D) is strongly associated with coronary heart disease. However, the molecular mechanism underlying coronary vascular pathology, especially coronary arterial smooth muscle pathology in human with T1D is incomplete. Vascular BK channels, composed of four pore-forming subunits (BK-α) and four regulatory subunits (BK-β1), are densely expressed in coronary artery smooth muscle cells (SMCs) and are a key determinant of coronary blood flow and cardiac function. Over the last 10 years, we and other investigators have demonstrated that coronary BK channel function is impaired in T1D animals due to increased oxidative stress and it contributes to a worse outcome in myocardial ischemia. However, most of our knowledge of coronary BK channel dysregulation in T1D is obtained from animals and most of studies are focused on the BK-β1 dysregulation in diabetes. The Sorbin and SH3 domain-containing protein 2 (Sorbs2) is a component of cytoskeleton proteins in vascular SMCs. Sorbs2 is abundantly expressed in cardiovascular tissues and is a downstream target of Nrf2. However, the role of Sorbs2 in vascular pathophysiology is unknown. We have exciting preliminary results showing that Sorbs2 interacts with BK-α and BK-β1 protein and regulates BK channel expression in coronary SMCs. Interestingly, Sorbs2 knockout mice share many common features of coronary BK channelopathy with diabetes, despite being normoglycemic and not obese, indicating that Sorbs2 deficiency is an independent risk of vascular BK channelopathy. Importantly, Sorbs2 expression is significantly reduced in coronary arteries of patients with T1D. Unlike T2D patients, the expression of BK-α, but that of BK- β1, is markedly reduced in the coronary SMCs of patients with T1D. However, the role of Sorbs2 on coronary BK channelopathy and vasculopathy of human T1D has not been established, and the underlying mechanisms regarding the downregulation of BK-α expression in coronary SMCs of T1D patients is unclear. In this project, we will take advantage of the availability of human coronary arteries from T1D patients who are scheduled for cardiac surgery at Mayo Clinic in Rochester (MN) to test our hypothesis that downregulation of Sorbs2 expression contributes to BK channel and vascular dysfunction in the coronary arteries of T1D patients and increase of Sorbs2 expression by pharmacological Nrf2 activation protects coronary BK channel function and vasoreactivity in human tissues with T1D. Results from this study will provide novel insights into the molecular mechanisms underlying BK channelopathy and coronary vasculopathy in T1D and may help develop new strategies for the treatment of cardiovascular complications in T1D patients.