Critical role of Mitochondrial Fission/Fusion in Regulation of Microvascular Endothelial Function

线粒体裂变/融合在微血管内皮功能调节中的关键作用

• 批准号: 10180126
• 负责人: Andreas M Beyer
• 金额: $ 53.71万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10180126
• 关键词: Acute; Adipose tissue; Age; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular Pathology; Cell Proliferation; Cells; Chimeric Proteins; Chronic; Coronary; Coronary Arteriosclerosis; Coronary heart disease; Data; Development; Dilator; Disease; Dynamin; Elements; Endothelial Cells; Endothelium; Equilibrium; Exhibits; Exposure to; Functional disorder; Generations; Genetic; Glucose; Goals; Human; Hydrogen Peroxide; Hypoxia; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Investigation; Learning; Link; Mediating; Mediator of activation protein; Microcirculation; Mitochondria; Morphology; Nitric Oxide; Outcome; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Pharmacology; Phenotype; Physiological; Process; Production; Proteins; Publishing; Regional Blood Flow; Regulation; Resistance; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Smooth Muscle; Stimulus; Stress; Testing; Therapeutic; Tissues; Toxic effect; Up-Regulation; Vascular Endothelium; Vasodilator Agents; Vasomotor; Work; acute stress; arteriole; base; cancer therapy; cardioprotection; cardiovascular risk factor; clinical Diagnosis; improved; knock-down; novel; overexpression; paracrine; preconditioning; pressure; prevent; response; stressor; tissue injury; tool; treatment strategy; vascular injury; vascular stress

Increased age, presence of other cardiovascular risk factors or previous treatment with anti-cancer therapy are among the leading risk factors for development of coronary artery disease (CAD). While CAD is traditionally viewed as a large vessel disease substantial recent data indicate that impaired microvascular function contributes substantially to pathophysiology and outcomes in cardiovascular disease. Subjects with a clinical diagnosis of CAD exhibit loss of NO-mediated microvascular flow-mediated dilation (FMD) concurrent with upregulation of mitochondrial hydrogen peroxide (H2O2), promoting local inflammation and cellular proliferation. Understanding the contributing mechanisms that regulate the switch from NO to H2O2 may help to reduce the risk of tissue injury from vascular paracrine redox toxicity. We have identified several components of the signaling pathway that changes the mediator of FMD from NO to H2O2. The common feature of each of these pathways is excess endothelial mitochondrial ROS generation. Mitochondrial fission and fusion, known regulators of ROS production, are tightly regulated by a group of pro- fission and pro-fusion proteins suggesting the possibility that these factors determine the mediator of FMD in the human microvasculature, an unexplored question. The goal of this study is to test the hypothesis that mitochondrial fission/fusion is critically linked to the mediator of FMD in the human microcirculation. Based on preliminary data we expect that regulators of fission/fusion are fundamental mediators of mitochondrial ROS production and determinants of whether shear elicits release of endothelial NO or H2O2. Mitochondria and ROS are also involved in hypoxic preconditioning (HPC), a stimulus that improves tissue tolerance to stressors and protects against disease. Very little is known about HPC and vascular protection with no studies in the microcirculation. Our preliminary data support a role for mitochondrial fission and fusion in mediating HPC. This potential mechanism for HPC induced vascular protection will be explored. We will study fresh human coronary and adipose arterioles and primary human microvascular endothelial cells in vitro using pharmacological and genetic tools to manipulate fission and fusion mediators and determine how these changes contribute to alterations in mechanisms of FMD observed in CAD or after acute stress (elevated glucose, intraluminal pressure). We will test the overreaching hypothesis that mitochondrial fission is associated with H2O2 while mitochondrial fusion promotes physiological NO mediated dilation to flow. Aim 1: Changes in fission/fusion or its regulators are necessary and sufficient to explain the transition in the mediator of FMD from NO to H2O2 during CAD or vascular stress (IILP or HG) Aim 2: Investigate whether the mechanism by which hypoxic vascular preconditioning improves microvascular function after acute stress (IILP, HG) or in subjects with CAD involves an increase in mitochondrial fusion.

增加年龄，其他心血管危险因素或抗癌治疗的先前治疗是 在冠状动脉疾病（CAD）发展的主要危险因素之一。而CAD传统上是 被视为大容器疾病，最近的数据表明微血管功能受损 在心血管疾病中的病理生理学和结果基本上做出了贡献。具有临床的受试者 CAD的诊断表现出无介导的微血管流动介导的扩张（FMD）的丧失与 线粒体过氧化氢（H2O2）的上调，促进局部炎症和细胞增殖。 了解调节从NO到H2O2转换的贡献机制可能有助于减少 血管旁分泌氧化还原毒性因组织损伤的风险。 我们已经确定了信号通路的几个组件，这些组件将FMD的介体从NO变为 H2O2。这些途径中每一种的共同特征是过量的内皮线粒体ROS产生。 线粒体裂变和融合（已知的ROS产生调节剂）受一组促值的严格调节 裂变和促融合蛋白表明这些因素决定了FMD介体的可能性 人类微脉管系统，一个未开发的问题。这项研究的目的是检验以下假设 线粒体裂变/融合与人类微循环中FMD的介体密切相关。基于 初步数据我们期望裂变/融合的调节因子是线粒体ROS的基本介质 生产和决定剪切是否引发内皮NO或H2O2的释放。 线粒体和ROS也参与缺氧预处理（HPC），这是一种改善组织的刺激 对压力源的耐受性并预防疾病。关于HPC和血管保护的知之甚少 没有微循环的研究。我们的初步数据支持线粒体裂变和融合的作用 介导HPC。将探索这种HPC诱导血管保护的潜在机制。我们将学习 新鲜的人类冠状动脉和脂肪动脉和原发性人类微血管内皮细胞体外使用 处理裂变和融合介质的药理和遗传工具，并确定这些改变如何变化 有助于改变CAD或急性应激后观察到的FMD机制的改变（葡萄糖升高， 腔内压力）。我们将测试线粒体裂变与H2O2相关的过度假设 线粒体融合会促进生理无介导的流量扩张。 目标1：裂变/融合或其调节剂的变化是必要的，足以解释 FMD介体在CAD或血管应力（IILP或HG）中从NO到H2O2过渡（IILP或HG） 目标2：研究低氧血管预处理的机制是否有所改善 急性应激（IILP，HG）或CAD受试者的微血管功能涉及增加 线粒体融合。