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: 10705359
• 负责人: Liya Yin
• 金额: $ 61.24万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705359
• 关键词: 3-Dimensional; Ablation; Acetylcholine; Address; Adult; Anti-Inflammatory Agents; Biology; Blood Vessels; Blood flow; Bone Marrow Cells; CD34 gene; Cardiac; Cardiovascular Pathology; Cardiovascular system; Cells; Clinical; Contrast Echocardiography; Coronary; Coronary Arteriosclerosis; Coronary Circulation; Coronary artery; Data; Diabetes Mellitus; Diabetic mouse; Dilator; Discipline; Disease; Disease Progression; EFRAC; Echocardiography; Endothelial Cells; Endothelium; Endothelium-Dependent Relaxing Factors; Exhibits; Failure; Functional disorder; Genetic; Heart failure; Hemostatic function; Hydrogen Peroxide; Hypertension; Impairment; Injury; Ischemia; Knock-out; Lead; Measurement; Mediating; Mediator of activation protein; Methods; MicroRNAs; Microcirculation; Microvascular Dysfunction; Modeling; Molecular; Mus; Myocardial; Myocardial Ischemia; Myocardial perfusion; Myocardium; Nitric Oxide; PECAM1 gene; Pathogenicity; Pathologic; Pathology; Patients; Perfusion; Physiologic pulse; Physiological; Physiology; Prognosis; Regulation; Relaxation; Reporting; Role; Stem cell transplant; Testing; Therapeutic; Tissues; Vasodilation; Vasodilator Agents; Work; 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; pre-clinical; preservation; prevent; restoration; transcriptome sequencing

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, which is characterized by impaired acetylcholine-induced endothelial- dependent relaxation. Impaired endothelium-dependent vasodilation (EDD) decreases coronary blood flow and myocardium perfusion, leading to myocardial ischemia even 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 coronary vasodilation. This application will address the underlying mechanism of how miR-21 regulates the NO to H2O2 switches in diabetes and the pathological consequence of the switch in DCM. We hypothesize that restoring “normal” coronary microvascular function (restoring endothelial dilation) 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, 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.

冠状动脉微血管功能障碍（CMD）与冠状动脉疾病（CAD）有关， 糖尿病性心肌病（DCM）、非阻塞性冠状动脉缺血（INOCA），以及 HFpEF（射血分数保留的心力衰竭）。糖尿病患者的冠状动脉 内皮功能障碍，其特征是乙酰胆碱诱导的内皮功能受损。 依赖松弛内皮依赖性血管舒张功能受损（EDD）降低了冠状动脉 血流和心肌灌注，导致心肌缺血，即使没有阻塞性 冠状动脉然而，冠状动脉内皮扩张受损的潜在机制， DCM尚未完全理解。我们的初步研究发现，NO是内皮细胞的介质， 依赖性扩张（EDD）在健康小鼠的小冠状动脉。然而，在糖尿病小鼠中， 我们观察到过氧化氢（H2 O2）是主要的内皮依赖性血管舒张剂。 这种独特的临床前糖尿病模型概括了CAD中NO转化为H2 O2的临床观察 患者 此外，我们发现miR-21的缺乏恢复了NO依赖的冠状动脉血管舒张。 本申请将阐述miR-21如何调节NO转化为H2 O2的潜在机制 糖尿病的转变和扩张型心肌病转变的病理后果。我们假设 恢复“正常”冠状动脉微血管功能（恢复内皮扩张）， 调节miR-21可以改善糖尿病性心肌病（被认为是一种疾病， 与冠状动脉微血管功能受损有关）。我们将通过一个 跨学科的方法，包括一系列的方法和学科，从分子和 细胞分析、血管生物学、生理学和病理生理学， 冠状动脉微血管功能障碍的新机制，如组织特异性敲除和 使用3D荧光成像进行谱系追踪，测量血管舒张和心肌血液 对比超声心动图体内血流和心脏功能超声心动图沿着 RNA-seq、sc RNA-seq等。完成这个项目可能会带来一种新的治疗策略 微血管功能障碍和糖尿病心肌病，改善心血管 糖尿病的预后