MRI in mouse models of heart disease

项目摘要 冠状动脉微血管疾病（CMD）越来越多地被认为是心力衰竭的主要原因 肥胖症和糖尿病患者中。最近的研究表明，在没有阻塞性心外膜的情况下， 冠状动脉疾病（CAD），通过PET或MRI评估的心肌灌注储备（MPR）受损是一种 CMD的功能后果，并预测不良心脏事件的高风险。目前，与CAD不同， 对于CMD没有确定的治疗。从机制上讲，肥胖和糖尿病会导致肾素的激活- 血管紧张素-醛固酮系统，除了血管紧张素II，基础研究表明， 醛固酮和相应的盐皮质激素受体在血管氧化应激和炎症中的作用， 导致内皮功能障碍、血管平滑肌功能受损和血管舒张，以及血管周围 离体小动脉纤维化。翻译这些发现，初步临床成像研究表明， 盐皮质激素受体拮抗剂（MRA）可改善超重/肥胖和糖尿病患者受损的MPR 没有CAD虽然很有希望，但MRA在以下疾病中的治疗作用的具体作用机制尚不清楚： 改善MPR还不完全清楚，数据表明MRA可能对女性无效， 关于治疗效果是否扩展到外周动脉微血管功能障碍的数据相互矛盾 疾病我们已经开发了可重复的定量灌注MRI方法的小鼠和建立小鼠 喂食高脂饮食（HFD）作为肥胖、II型糖尿病、无CAD的CMD和受损MPR的模型。我们也 显示，与人类一样，依普利酮（EPL），一种选择性MRA，可改善雄性HFD小鼠的MPR。的目标 目前的建议是在HFD小鼠中开发和使用MRI以及药理学和遗传学操作 证明血管平滑肌盐皮质激素受体和氧化应激在 由于肥胖和糖尿病导致MPR受损，并阐明有关MRA是否 对女性和外周微血管功能障碍有效。

Project Summary Coronary microvascular disease (CMD) is increasingly recognized as a major contributor to heart failure in patients with obesity and diabetes. Recent studies have shown that, in the absence of obstructive epicardial coronary artery disease (CAD), impaired myocardial perfusion reserve (MPR) assessed by PET or MRI is a functional consequence of CMD and predicts a high risk of adverse cardiac events. Presently, unlike for CAD, there is no established treatment for CMD. Mechanistically, obesity and diabetes cause activation of the renin- angiotensin-aldosterone system and, in addition to angiotensin II, basic research demonstrates a central role of aldosterone and the corresponding mineralocorticoid receptor in vascular oxidative stress and inflammation, resulting in endothelial dysfunction, impaired vascular smooth muscle function and vasodilation, and perivascular fibrosis in excised isolated arterioles. Translating these findings, initial clinical imaging studies demonstrate that mineralocorticoid receptor antagonists (MRAs) improve impaired MPR in overweight/obese and diabetic patients without CAD. While promising, the specific mechanism of action underlying the therapeutic effects of MRAs in improving MPR is not fully understood, data suggest that MRAs may be ineffective in women, and there are conflicting data regarding whether the therapeutic effects extend to microvascular dysfunction in peripheral artery disease. We have developed reproducible quantitative perfusion MRI methods for mice and established mice fed a high-fat diet (HFD) as a model of obesity, type II diabetes, CMD without CAD, and impaired MPR. We also showed that, like in humans, eplerenone (EPL), a selective MRA, improves MPR in male HFD mice. The goals of the present proposal are to develop and use MRI and pharmacologic and genetic manipulations in HFD mice to prove the central roles of the vascular smooth muscle mineralocorticoid receptor and oxidative stress in impaired MPR due to obesity and diabetes, and to shed light on open questions concerning whether MRAs are effective in females and in peripheral microvascular dysfunction.