Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany.
Department of Cardiovascular Physiology, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
Cells. 2023 Jan 29;12(3):443. doi: 10.3390/cells12030443.
(1) Background: Diabetic cardiomyopathy is a major health problem worldwide. CTRP9, a secreted glycoprotein, is mainly expressed in cardiac endothelial cells and becomes downregulated in mouse models of diabetes mellitus; (2) Methods: In this study, we investigated the impact of CTRP9 on early stages of diabetic cardiomyopathy induced by 12 weeks of high-fat diet; (3) Results: While the lack of CTRP9 in knock-out mice aggravated insulin resistance and triggered diastolic left ventricular dysfunction, AAV9-mediated cardiac CTRP9 overexpression ameliorated cardiomyopathy under these conditions. At this early disease state upon high-fat diet, no fibrosis, no oxidative damage and no lipid deposition were identified in the myocardium of any of the experimental groups. Mechanistically, we found that CTRP9 is required for insulin-dependent signaling, cardiac glucose uptake in vivo and oxidative energy production in cardiomyocytes. Extensive RNA sequencing from myocardial tissue of CTRP9-overexpressing and knock-out as well as respective control mice revealed that CTRP9 acts as an anti-inflammatory mediator in the myocardium. Hence, CTRP9 knock-out exerted more, while CTRP9-overexpressing mice showed less leukocytes accumulation in the heart during high-fat diet; (4) Conclusions: In summary, endothelial-derived CTRP9 plays a prominent paracrine role to protect against diabetic cardiomyopathy and might constitute a therapeutic target.
(1) 背景：糖尿病性心肌病是全球范围内的一个主要健康问题。CTRP9 是一种分泌型糖蛋白，主要在心脏内皮细胞中表达，在糖尿病小鼠模型中表达下调；(2) 方法：在这项研究中，我们研究了 CTRP9 对 12 周高脂肪饮食诱导的糖尿病性心肌病早期阶段的影响；(3) 结果：尽管敲除小鼠缺乏 CTRP9 会加重胰岛素抵抗并引发舒张性左心室功能障碍，但 AAV9 介导的心脏 CTRP9 过表达在这些条件下改善了心肌病。在高脂肪饮食的早期疾病状态下，实验组的心肌中均未发现纤维化、氧化损伤或脂质沉积。从 CTRP9 过表达和敲除以及各自的对照小鼠的心肌组织进行的广泛 RNA 测序表明，CTRP9 是胰岛素依赖性信号、心脏体内葡萄糖摄取和心肌细胞氧化能量产生所必需的。因此，CTRP9 敲除小鼠表现出更多的炎症细胞积聚，而 CTRP9 过表达小鼠在高脂肪饮食期间心脏中的炎症细胞积聚较少；(4) 结论：总之，内皮细胞衍生的 CTRP9 发挥着重要的旁分泌作用，可预防糖尿病性心肌病，可能成为一种治疗靶点。
