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: 10677743
• 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/10677743
• 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; Cytoskeletal Proteins; Diabetes Mellitus; Diabetic Nephropathy; Down-Regulation; Event; Exhibits; FDA approved; Functional disorder; Human; Impairment; In Situ; Insulin-Dependent Diabetes Mellitus; Knockout Mice; Knowledge; Ligation; Mediating; Membrane; Membrane Proteins; Molecular; Myocardial Ischemia; Myocardial perfusion; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Oxidative Stress; Pathology; Patients; Physiology; Play; Proteins; Rattus; Regulation; Reporting; Research Personnel; Resolution; Risk; Risk Factors; Role; SH3 Domains; 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; novel therapeutic intervention; nuclear factor-erythroid 2; patch clamp; pharmacologic; preservation; protein expression; sorbin; treatment strategy; type I and type II diabetes; ultra high resolution; 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.

项目摘要 1型糖尿病（T1 D）与冠心病密切相关。然而，分子机制 潜在的冠状血管病理学，特别是人的冠状动脉平滑肌病理学， T1 D不完整血管BK通道由4个成孔亚基（BK-α）和4个调节性BK通道组成， BK-β1在冠状动脉平滑肌细胞（SMCs）中密集表达，是一种关键的免疫调节因子。 冠状动脉血流量和心脏功能的决定因素。在过去的10年里，我们和其他调查人员 已经证明T1 D动物的冠状动脉BK通道功能由于氧化性增加而受损， 应激，并导致心肌缺血的更差结果。然而，我们对 T1 D中的冠状动脉BK通道失调是从动物获得的，并且大多数研究集中在T1 D中的 糖尿病中BK-β1失调。Sorbin和含SH 3结构域的蛋白2（Sorbs 2）是 血管平滑肌细胞中的细胞骨架蛋白。Sorbs 2在心血管组织中大量表达， Nrf 2的下游靶点。然而，Sorbs 2在血管病理生理学中的作用尚不清楚。我们有 令人兴奋的初步结果表明，Sorbs 2与BK-α和BK-β1蛋白相互作用， 在冠状动脉SMC中的通道表达。有趣的是，Sorbs 2基因敲除小鼠具有许多共同的特征， 尽管血糖正常且不肥胖，但合并糖尿病的冠状动脉BK通道病表明Sorbs 2 缺乏是血管性BK通道病的独立风险。重要的是，Sorbs 2表达显著增加。 T1 D患者的冠状动脉减少。与T2 D患者不同，BK-α的表达，但BK- β1在T1 D患者的冠状动脉SMC中显著降低。然而，Sorbs 2在冠状动脉粥样硬化中的作用 人类T1 D的BK通道病和血管病尚未确定，其潜在机制 关于T1 D患者冠状动脉SMC中BK-α表达的下调尚不清楚。在本项目中， 我们将利用来自T1 D患者的人类冠状动脉的可用性， 在罗切斯特（MN）的马约诊所进行心脏手术，以检验我们的假设， 表达有助于T1 D患者冠状动脉中的BK通道和血管功能障碍， 通过药理学Nrf 2激活增加Sorbs 2表达保护冠状动脉BK通道功能， T1 D患者组织中的血管反应性。这项研究的结果将提供新的见解， T1 D患者BK通道病和冠状动脉血管病变的潜在机制，可能有助于开发新的 T1 D患者心血管并发症的治疗策略。

项目成果

Characterization of cardiac bradyarrhythmia associated with LGI1-IgG autoimmune encephalitis.

• DOI: 10.3389/fimmu.2022.948479
• 发表时间: 2022
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Zhao-Fleming, Hannah H.;Zahid, Anza;Lu, Tong;Sun, Xiaojing;Pittock, Sean J.;Lee, Hon-Chi;Dubey, Divyanshu
• 通讯作者: Dubey, Divyanshu