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

1 型糖尿病患者冠状动脉中的 Sorbs2 靶向和 BK 通道调节

• 批准号: 10507884
• 负责人: Tong Lu
• 金额: $ 68.84万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10507884
• 关键词: Animals; Atherosclerosis; Binding; Biological Assay; Biophysics; Biotinylation; Blood Glucose; Blood Vessels; Blood flow; Body Weight; Cardiac Surgery procedures; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Clinic; Clinical; Coronary; Coronary Circulation; Coronary artery; Coronary heart disease; Cytoskeleton; Diabetes Mellitus; Diabetic Nephropathy; Down-Regulation; Event; Exhibits; FDA approved; Functional disorder; Human; Impairment; In Situ; Insulin-Dependent Diabetes Mellitus; Knockout Mice; Knowledge; Lead; Ligation; Mediating; Membrane; Membrane Proteins; Molecular; Myocardial Ischemia; Myocardial perfusion; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Oxidative Stress; Pathology; Patients; Pharmacology; Physiology; Play; Proteins; Rattus; Regulation; Reporting; Research Personnel; Resolution; Risk; Risk Factors; Role; SH3 Domains; SORBS2 gene; Scaffolding Protein; Schedule; Signal Transduction; Site-Directed Mutagenesis; Smooth Muscle; Smooth Muscle Myocytes; Sulforaphane; Surface; Techniques; Technology; Tertiary Protein Structure; Testing; Therapeutic; Tissues; Vascular Diseases; Vascular Smooth Muscle; Vasodilation; Video Microscopy; arteriole; diabetic; diabetic patient; endothelial dysfunction; heart function; human tissue; improved; insight; large-conductance calcium-activated potassium channels; molecular targeted therapies; non-diabetic; novel; novel strategies; nuclear factor-erythroid 2; patch clamp; preservation; protein expression; sorbin; treatment strategy; type I and type II diabetes; vascular inflammation

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.

项目概要 1 型糖尿病 (T1D) 与冠心病密切相关，但其分子机制尚不清楚。 潜在的冠状血管病理学，尤其是人类冠状动脉平滑肌病理学 T1D 血管 BK 通道不完整，由四个成孔亚基 (BK-α) 和四个调节亚基组成。 亚基 (BK-β1) 在冠状动脉平滑肌细胞 (SMC) 中密集表达，是冠状动脉平滑肌细胞 (SMC) 的关键 在过去的 10 年里，我们和其他研究人员研究了冠状动脉血流量和心脏功能的决定因素。 已经证明，由于氧化增加，T1D 动物的冠状动脉 BK 通道功能受损 压力会导致心肌缺血的更糟糕的结果。 T1D 中冠状动脉 BK 通道失调是从动物身上获得的，大多数研究都集中在 糖尿病中的 BK-β1 失调包含 Sorbin 和 SH3 结构域的蛋白 2 (Sorbs2) 的组成部分。 血管 SMC 中的细胞骨架蛋白 Sorbs2 在心血管组织中大量表达，是一种 然而，Sorbs2 在血管病理生理学中的作用尚不清楚。 令人兴奋的初步结果表明，Sorbs2 与 BK-α 和 BK-β1 蛋白相互作用并调节 BK 冠状动脉 SMC 中隐含的通道表达，Sorbs2 敲除小鼠具有许多共同特征。 尽管血糖正常且不肥胖，但伴有糖尿病的冠状动脉 BK 通道病变表明 Sorbs2 缺乏是血管 BK 通道病变的独立风险，重要的是，Sorbs2 表达显着。 与 T2D 患者不同，T1D 患者冠状动脉中 BK-α 的表达减少，但 BK- 的表达减少。 T1D 患者冠状动脉 SMC 中的 β1 显着减少，但 Sorbs2 对冠状动脉的作用。 人类 T1D 的 BK 通道病变和血管病变尚未确定，其潜在机制尚未确定 关于 T1D 患者冠状动脉 SMC 中 BK-α 表达的下调尚不清楚。 我们将利用预定的 T1D 患者的人类冠状动脉 在罗彻斯特（明尼苏达州）梅奥诊所进行心脏手术，以检验我们的假设：Sorbs2 下调 表达导致 T1D 患者冠状动脉 BK 通道和血管功能障碍 通过药理学 Nrf2 激活增加 Sorbs2 表达可保护冠状动脉 BK 通道功能 T1D 人体组织的血管反应性这项研究的结果将为分子机制提供新的见解。 T1D 中 BK 通道病变和冠状血管病变的潜在机制，可能有助于开发新的 T1D 患者心血管并发症的治疗策略。