Endothelial function in human diabetes: role of mitochondrial fission proteins

人类糖尿病中的内皮功能：线粒体裂变蛋白的作用

• 批准号: 9888401
• 负责人: Michael E Widlansky
• 金额: $ 59.03万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888401
• 关键词: Acute; Arteries; Binding; Biological; Biological Assay; Biological Availability; Blindness; Blood Vessels; Cells; Chemicals; Chronic; Cytology; DOK1 gene; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Docking; Drug Design; Dynamin; Endothelial Cells; Endothelium; Enzymes; Event; Exposure to; Functional disorder; Future; Glucose; Goals; Grant; Guanosine Triphosphate Phosphohydrolases; Health; Hela Cells; Human; Hydrolysis; Hyperglycemia; Hypoglycemia; Impairment; Individual; Kidney Diseases; Lead; Ligands; Measures; Mediating; Membrane; Microvascular Dysfunction; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Myocardial Infarction; Neuropathy; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Outer Mitochondrial Membrane; Oxidative Stress; Pathway interactions; Patients; Peripheral Vascular Diseases; Pharmaceutical Chemistry; Pharmacology; Positioning Attribute; Preclinical Testing; Prevalence; Process; Production; Proteins; Reactive Oxygen Species; Role; Secondary to; Stroke; Structure; Test Result; Testing; Therapeutic; Therapeutic Intervention; Tissues; Vascular Diseases; Vasodilation; arteriole; base; clinically relevant; combat; cost; design; diabetic patient; drug testing; effective therapy; efficacy testing; endothelial dysfunction; glycemic control; human subject; in vitro Assay; in vitro activity; in vitro testing; in vivo; inhibitor/antagonist; innovation; macrovascular disease; mitochondrial dysfunction; mortality; new therapeutic target; novel; novel therapeutic intervention; pandemic disease; prevent; public health relevance; small molecule; translational approach; vascular endothelial dysfunction; vascular inflammation

 DESCRIPTION (provided by applicant): The prevalence of diabetes (DM) worldwide has soared above 380 million individuals. The primary causes of morbidity and mortality in these patients are diabetes-related macrovascular and microvascular disease. DM vascular disease has critical pathophysiological differences from vascular disease seen in non-DM patients. Currently therapies to combat vascular disease are significantly less effective in DM patients compared to non-DM patients. Novel therapies targeted at disrupting pathophysiological pathways of particular importance in DM vascular disease may offer significant benefits for the reduction of adverse vascular events in DM. DM vascular disease begins with the development of vascular endothelial dysfunction-a state characterized by increased vascular inflammation and increased vasoconstrictive and pro-thrombotic tendencies. In DM, we and others have discovered endothelial dysfunction can be initiated by critical changes in endothelial mitochondrial function occurring secondary to excessive mitochondrial fission. These changes appear both following acute exposure to abnormal glucose as well as being evident during the chronic abnormal glucose exposures of DM. Our preliminary data suggest both acute impairment of endothelial function by high or low glucose exposure and chronic DM endothelial dysfunction occur through a common mechanism-the activation and binding of dynamin-related protein-1 (Drp1), a cytosolic-based GTPase enzyme, to docking proteins located on the outer mitochondrial membrane. This binding initiates excessive mitochondrial fission and triggers mitochondrial and endothelial dysfunction. Further, our preliminary data strongly suggest Fis1 is the critical Drp1 docking protein in this process. This application employs an innovative translational approach that uniquely combines critical pharmacological and molecular studies targeting the Drp1-Fis1 interaction in intact human vessels and endothelial cells from human subjects with structure-based drug design and testing of resulting compounds in relevant patient-derived tissues. Our approach holds great promise to lead directly to identifying a first-i-class pharmacological agent that could significantly reduce heart attacks, strokes, peripheral vascular disease, renal disease, blindness, and neuropathy in the world's nearly 400 million cases of diabetes. In Aim 1, we will determine whether acute in vivo exposure to high or low glucose levels induces mitochondrial fission and excess mitochondrial reactive oxygen species production. Further, we will determine whether impairment of endothelium-dependent vasodilation and nitric oxide (NO) bioavailability in intact arterioles from DM patients is Drp1 and/or Fis1-dependent manner. In Aim 2, we will determine whether the chronic impairment of endothelium-dependent vasodilation and NO bioavailability in intact arterioles from human with DM can be reversed by suppression of Fis1 and/or Drp1 expression. In Aim 3, we will identify small molecules to that specifically disrupt the Drp1-Fis1 interaction, validate these findings, an test the efficacy these small molecules on ex vivo human arterioles from DM subjects.

 描述（由申请人提供）：全球糖尿病 (DM) 患病率已飙升至 3.8 亿以上。这些患者发病和死亡的主要原因是糖尿病相关的大血管和微血管疾病。糖尿病血管疾病与非糖尿病患者的血管疾病具有重要的病理生理学差异。目前，与非糖尿病患者相比，针对糖尿病患者的血管疾病治疗效果明显较差。旨在破坏对 DM 血管疾病特别重要的病理生理学途径的新疗法可能会为减少 DM 不良血管事件带来显着益处。 DM 血管疾病始于血管内皮功能障碍的发展，这种状态的特征是血管炎症增加以及血管收缩和促血栓形成倾向增加。在糖尿病中，我们和其他人发现内皮功能障碍可能是由线粒体过度分裂继发的内皮线粒体功能的关键变化引起的。这些变化不仅在急性暴露于异常葡萄糖后出现，而且在糖尿病慢性异常葡萄糖暴露期间也很明显。我们的初步数据表明，高或低葡萄糖暴露引起的内皮功能急性损伤和慢性 DM 内皮功能障碍都是通过一个共同的机制发生的，即动力相关蛋白 1 (Drp1)（一种基于细胞质的 GTP 酶）的激活和结合，与位于线粒体外膜上的对接蛋白结合。这种结合引发过度的线粒体裂变并引发线粒体和内皮功能障碍。此外，我们的初步数据强烈表明 Fis1 是该过程中关键的 Drp1 对接蛋白。该应用采用创新的转化方法，独特地将针对完整人体血管和人类受试者内皮细胞中 Drp1-Fis1 相互作用的关键药理学和分子研究与基于结构的药物设计和相关患者来源组织中所得化合物的测试相结合。我们的方法有望直接识别出一种一流的药物，可以显着减少全球近 4 亿糖尿病病例的心脏病、中风、周围血管疾病、肾脏疾病、失明和神经病变。在目标 1 中，我们将确定体内急性暴露于高或低葡萄糖水平是否会诱导线粒体裂变和过量线粒体活性氧的产生。此外，我们将确定 DM 患者完整小动脉中内皮依赖性血管舒张和一氧化氮 (NO) 生物利用度的损害是否是 Drp1 和/或 Fis1 依赖性方式。在目标 2 中，我们将确定 DM 患者完整小动脉中内皮依赖性血管舒张和 NO 生物利用度的慢性损害是否可以通过抑制 Fis1 和/或 Drp1 表达来逆转。在目标 3 中，我们将鉴定特异性破坏 Drp1-Fis1 相互作用的小分子，验证这些发现，并测试这些小分子对来自 DM 受试者的离体人小动脉的功效。

项目成果

Finding Needles in the Gut Microbiota's Haystack.

• DOI: 10.1161/circresaha.122.322354
• 发表时间: 2023-01
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Michael Aljadah;Michael E. Widlansky

Pandemic Perspective: Commonalities Between COVID-19 and Cardio-Oncology.

大流行视角：COVID-19与心脏肿瘤学之间的共同点。

• DOI: 10.3389/fcvm.2020.568720
• 发表时间: 2020
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6
• 作者: Brown SA;Zaharova S;Mason P;Thompson J;Thapa B;Ishizawar D;Wilkes E;Ahmed G;Rubenstein J;Sanchez J;Joyce D;Kalyanaraman B;Widlansky M
• 通讯作者: Widlansky M