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：
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
项目类别：
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

项目摘要

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.

项目概要冠状动脉微血管功能障碍（CMD）与冠状动脉疾病（CAD）相关，糖尿病心肌病 (DCM)、非阻塞性冠状动脉缺血 (INOCA) 和 HFpEF（射血分数保留的心力衰竭）糖尿病患者表现出冠状动脉疾病。内皮功能障碍，其特征是乙酰胆碱诱导的内皮依赖性受损内皮依赖性血管舒张（EDD）受损会降低冠状动脉血流量。和心肌灌注，导致心肌缺血而不阻塞冠状动脉。然而，DCM 中冠状动脉内皮扩张受损的潜在机制尚不完全清楚。我们的初步研究发现，NO 是内皮依赖性扩张的介质。（EDD）在健康小鼠的小冠状动脉中然而，在糖尿病小鼠中，我们观察到这一点。过氧化氢（H2O2）是一种主要的内皮依赖性血管扩张剂。临床前糖尿病模型概括了 CAD 患者中 NO 到 H2O2 的临床观察。此外，我们发现 miR-21 的缺陷可以恢复分离的 NO 依赖性血管舒张功能。饮食诱发的糖尿病小鼠的冠状动脉该应用将解决功能性问题。 miR-21 调节的 NO 向 H2O2 转换对心肌血流量和心脏功能的影响我们致力于恢复“正常”冠状动脉。通过调节 miR-21can 恢复微血管功能（恢复内皮依赖性血管舒张）改善糖尿病心肌病（被认为是一种与冠状动脉受损有关的疾病）我们将通过跨学科的方法来检验我们的假设。涵盖分子和细胞分析以及血管分析等一系列方法和学科生物学到生理学和病理生理学，引发了对新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追踪 3D荧光成像，测量体内血管舒张和心肌血流量通过超声心动图与 RNA-seq、sc 对比超声心动图和心脏功能 RNA-seq等。完成这个项目可能会带来治疗微血管的新策略功能障碍和糖尿病心肌病，改善糖尿病心血管预后。