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

基本信息

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
项目类别：
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

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

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项目摘要

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 - 依赖的放松。受损的内皮依赖性血管舒张（EDD）降低冠状动脉血流和心肌灌注，即使没有阻塞性，也会导致心肌缺血冠状动脉。但是，冠状动脉内皮词典的潜在机制在 DCM尚未完全理解。我们的初步研究发现，NO是山上的介体健康小鼠中小冠状动脉的依赖性词典（EDD）。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。如此独特的临床前糖尿病模型概括了CAD中H2O2 NO的临床观察患者。此外，我们发现miR-21的缺乏恢复了无依赖性的冠状动脉血管舒张。该应用程序将解决miR-21如何调节NO的基本机制糖尿病的开关和DCM开关的病理后果。我们假设通过调节miR-21CAN改善糖尿病心肌病（被认为是一种疾病）与冠状动脉微血管功能受损有关）。我们将通过跨学科方法包括分子和分子的一系列方法和学科细胞分析，生理学和病理生理学的血管生物学，引发了研究冠状动脉微血管功能障碍的新型机制，例如组织特异性敲除和使用3D荧光成像，血管舒张和心肌血液测量的谱系跟踪对比的超声心动图和心脏功能通过超声心动图和心脏功能的流量以及 RNA-Seq，SC RNA-Seq等微血管功能障碍和糖尿病性心肌病，并改善心肌血管糖尿病的预后。