Insights into Coronary Microvascular Dysfunction in Diabetic Cardiomyopathy

项目摘要 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，特征为乙酰胆碱诱导的内皮依赖性受损 放松.内皮依赖性血管舒张功能（EDD）受损减少冠状动脉血流量 和心肌灌注，导致心肌缺血而没有冠状动脉阻塞。 然而，DCM中冠状动脉内皮舒张功能受损的潜在机制尚不完全清楚， 明白我们的初步研究发现NO是内皮依赖性舒张的介质 (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， 过氧化氢（H2 O2）是主要的内皮依赖性血管扩张剂。这样一个独特 临床前糖尿病模型概括了CAD患者中NO转化为H2 O2的临床观察。 此外，我们发现miR-21的缺乏恢复了孤立性心肌细胞中NO依赖性血管舒张， 饮食诱导的糖尿病小鼠的冠状小动脉。该应用程序将解决功能 miR-21调节的心肌血流和心脏中NO向H2 O2转换的结果 功能和潜在机制。我们假设恢复“正常”冠状动脉 微血管功能（恢复内皮依赖性血管舒张）通过调节miR-21可以 改善糖尿病性心肌病（被认为是与受损的冠状动脉相关的疾病） 微血管功能）。我们将通过跨学科的方法来检验我们的假设 包括一系列的方法和学科，从分子和细胞分析， 生物学到生理学和病理生理学，产生了一种新的机制的研究， 冠状动脉微血管功能障碍，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， 通过超声心动图沿着与RNA-seq，sc对比超声心动图和心功能 RNA-seq等。完成这一项目可能会带来一种治疗微血管的新策略 改善糖尿病心血管预后。

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.