Insights into Coronary Microvascular Dysfunction in Diabetic Cardiomyopathy

糖尿病心肌病冠状动脉微血管功能障碍的见解

• 批准号: 10657041
• 负责人: Liya Yin
• 金额: $ 64.45万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657041
• 关键词: 3-Dimensional; Ablation; Acetylcholine; Adult; Anti-Inflammatory Agents; Antioxidants; Biology; Blood Vessels; Blood flow; Bone Marrow Cells; Cardiac; Cardiovascular Pathology; Cardiovascular system; Cells; Clinical; Consensus; Contrast Echocardiography; Coronary; Coronary Arteriosclerosis; Coronary artery; Data; Development; Diabetes Mellitus; Diabetic mouse; Diet; Discipline; Disease; Disease Progression; EFRAC; Echocardiography; Endothelium; Endothelium-Dependent Relaxing Factors; Exhibits; Failure; Functional disorder; Genetic; Heart failure; Hydrogen Peroxide; Hypertension; Impairment; Inflammatory; Injury; Ischemia; Knock-out; Knockout Mice; Measurement; Mediating; Mediator; Methods; MicroRNAs; Microcirculation; Microvascular Dysfunction; Modeling; Molecular; Mus; Myocardial; Myocardial Ischemia; Myocardial perfusion; Myocardium; Nitric Oxide; Oxidative Stress; Pathogenicity; Pathology; Patients; Perfusion; Peroxisome Proliferator-Activated Receptors; Physiologic pulse; Physiology; Production; Prognosis; Reactive Oxygen Species; Relaxation; Reporting; Role; Stem cell transplant; Testing; Therapeutic; Tissues; Vasodilation; Vasodilator Agents; arteriole; diabetic; diabetic cardiomyopathy; diabetic patient; endothelial dysfunction; endothelial stem cell; fluorescence imaging; heart function; improved; in vivo; insight; interdisciplinary approach; mortality; novel; novel therapeutic intervention; pharmacologic; pre-clinical; preservation; prevent; restoration; self-renewal; thrombotic; transcriptome sequencing

Project Summary Coronary microvascular dysfunction (CMD) is associated with coronary artery diseases (CAD), diabetic cardiomyopathy (DCM), ischemia with the non-obstructive coronary artery (INOCA), and HFpEF (heart failure with preserved ejection fraction). Patients with diabetes exhibit coronary endothelial dysfunction, characterized by impaired acetylcholine-induced endothelial-dependent relaxation. Impaired endothelium-dependent vasodilation (EDD) decreases coronary blood flow and myocardium perfusion, leading to myocardial ischemia without an obstructive coronary artery. However, the underlying mechanism of impaired coronary endothelial dilation in DCM is not fully understood. Our preliminary study finds that NO is the mediator of endothelium-dependent dilation (EDD) in small coronary arteries in healthy mice. However, in diabetic mice, we observe that hydrogen peroxide (H2O2) is the principal endothelial-dependent vasodilator. Such a unique preclinical diabetic model recapitulates a clinical observation of NO to H2O2 in CAD patients. Moreover, we find a deficiency of miR-21 that restores the NO-dependent vasodilation in isolated coronary arterioles of diet-induced diabetic mice. This application will address the functional consequence of the miR-21-regulated NO to H2O2 switch in myocardial blood flow and cardiac function and the underlying mechanism. We hypothesize that restoring “normal” coronary microvascular function (restoring endothelial-dependent vasodilation) by modulating miR-21can ameliorate diabetic cardiomyopathy (which is thought to be a disease related to impaired coronary microvascular function). We will test our hypothesis by an interdisciplinary approach encompassing a range of methods and disciplines from molecular and cell analyses and vascular biology to physiology and pathophysiology, engendering the study of a novel mechanism of coronary microvascular dysfunction, such as tissue-specific knockouts and lineage tracing with 3D fluorescent imaging, measurement of vasodilation and myocardial blood flow in vivo by contrast echocardiography and cardiac function by echocardiography along with RNA-seq, sc RNA-seq, etc. Completing this project may lead to a new strategy to treat microvascular dysfunction and diabetic cardiomyopathy and improve the cardiovascular prognosis of diabetes.

项目摘要 冠状动脉功能障碍（CMD）与冠状动脉疾病（CAD）相关， 糖尿病性心肌病（DCM），缺血，具有非刺激性冠状动脉（Inoca）和 HFPEF（心力衰竭，保留射血分数）。糖尿病患者表现出冠状动脉 内皮功能障碍，其特征是乙酰胆碱诱导的内皮依赖性 松弛。受损的内皮依赖性血管舒张（EDD）下降冠状动脉血流 和心肌灌注，导致心肌缺血没有阻塞性冠状动脉。 但是，DCM中冠状动脉内皮词典受损的基本机制尚未完全 理解齿。我们的初步研究发现NO是内皮依赖性词典的介体 （EDD）在健康小鼠的小冠状动脉中。但是，在糖尿病小鼠中，我们观察到 过氧化氢（H2O2）是主要内皮依赖性血管扩张剂。如此独特 临床前糖尿病模型概括了CAD患者对H2O2 NO的临床观察。 此外，我们发现miR-21的缺陷恢复了分离的无依赖性血管舒张 饮食诱导的糖尿病小鼠的冠状动脉。此应用程序将解决功能 在心肌流动和心脏中对H2O2开关的miR-21调节的结果 功能和基本机制。我们假设恢复“正常”冠状动脉 通过调节miR-21can，微血管功能（恢复内皮依赖性血管舒张） 改善糖尿病心肌病（被认为是与冠状动脉受损有关的疾病 微血管功能）。我们将通过跨学科方法检验我们的假设 包括分子和细胞分析以及血管的一系列方法和学科 生理学和病理生理学生物学，引发了一种新型机制的研究 冠状动脉微血管功能障碍，例如组织特异性敲除和谱系跟踪 3D荧光成像，血管舒张的测量和体内心肌血流 对比的超声心动图和心脏功能超声心动图以及RNA-seq，SC RNA-seq等完成此项目可能会导致一种治疗微血管的新策略 功能障碍和糖尿病心肌病并改善糖尿病的心血管预后。