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)相关， 糖尿病心肌病(DCM)，非梗阻性冠状动脉缺血(INOCA)，以及 HFpEF(射血分数保留的心力衰竭)。糖尿病患者表现为冠状动脉病变 以乙酰胆碱诱导的内皮依赖性受损为特征的内皮功能障碍 放松一下。内皮依赖性血管扩张受损(EDD)减少冠脉血流量 和心肌灌注，导致心肌缺血而不出现冠状动脉梗阻。 然而，扩张型心肌病冠状动脉内皮细胞扩张受损的潜在机制尚不完全。 明白了。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 过氧化氢(H_2O_2)是主要的内皮依赖性血管扩张剂。这样一个独一无二的 临床前糖尿病模型总结了冠心病患者NO至H_2O_2的临床观察。 此外，我们还发现了miR-21的缺陷，该缺陷可以恢复NO依赖的血管扩张。 饮食诱导糖尿病小鼠的冠状小动脉。这个应用程序将解决功能 MiR-21调节的NO向H_2O_2转换对心肌血流量和心脏功能的影响 功能和潜在的机制。我们假设恢复“正常”冠状动脉 通过调节miR-21can实现微血管功能(恢复内皮依赖性血管扩张) 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)。我们将用跨学科的方法来检验我们的假设。 包括从分子和细胞分析到血管的一系列方法和学科 生物学转向生理学和病理生理学，产生了一种新的发病机制的研究 冠状动脉微血管功能障碍，如组织特异性基因敲除和血统追踪 三维荧光成像，测量血管扩张和在体心肌血流量 超声心动图与核糖核酸序列联用的声学造影及心功能研究 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变，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.