Background:Cardiac remodeling is modulated by overnutrition or starvation. The adipokine leptin mediates energy balance between adipose tissue and brain. Leptin and its receptors are expressed in the heart.Methods and Results:To examine the importance of endothelial leptin signaling in cardiac hypertrophy, transverse aortic constriction was used in mice with inducible endothelium-specific deletion of leptin receptors (End.LepR-KO) or littermate controls (End.LepR-WT). End.LepR-KO was associated with improved left ventricular function (fractional shortening, 28.4% versus 18.8%; P=0.0114), reduced left ventricular dilation (end-systolic inner left ventricular diameter, 3.59 versus 4.08 mm; P=0.0188) and lower heart weight (133 versus 173 mg; P<0.0001) 20 weeks after transverse aortic constriction. Histology and quantitative polymerase chain reaction analysis confirmed reduced cardiomyocyte hypertrophy. STAT3 (signal transducer and activator of transcription) activation was reduced, and Akt (protein kinase B) and mTOR (mammalian target of rapamycin) phosphorylation after transverse aortic constriction were blunted in End.LepR-KO hearts. Elevated LC3 (microtubule associated protein 1 light chain 3)-I/-II conversion (P=0.0041) and increased (LC3II-positive) endothelial cells (P=0.0042) in banded hearts of End.LepR-KO mice suggested improved cardiac angiogenesis because of activated autophagy. Microscopy confirmed autophagosome accumulation after genetic or small interfering RNA-mediated LepR downregulation. Enhanced sprouting angiogenesis was observed in endothelial cells (P<0.0001) and aortic rings (P=0.0060) from End.LepR-KO mice, and murine and human endothelial sprouting angiogenesis was reduced after mTOR inhibition using rapamycin or autophagy inhibition using 3-methyladenine. Banded End.LepR-KO mouse hearts exhibited less apoptosis (P=0.0218), inflammation (P=0.0251), and fibrosis (P=0.0256). Reduced endothelial autophagy was also observed in myocardial biopsies of heart failure patients with cardiac fibrosis.Conclusions:Our findings suggest that endothelial leptin signaling contributes to cardiac fibrosis and functional deterioration by suppressing endothelial autophagy and promoting endothelial dysfunction in a chronic pressure overload model.

中文翻译：

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内皮瘦素受体缺失通过抑制 Akt/mTOR 信号传导促进压力过载后的心脏自噬和血管生成

背景：心脏重塑受营养过剩或饥饿的调节。脂肪因子瘦素介导脂肪组织和大脑之间的能量平衡。瘦素及其受体在心脏中表达。 方法和结果：为了检查内皮瘦素信号传导在心脏肥大中的重要性，在具有可诱导内皮特异性瘦素受体缺失 (End.LepR-KO) 或同窝对照（End.LepR-WT）。End.LepR-KO 与左心室功能改善（部分缩短，28.4% 对 18.8%；P = 0.0114）、左心室扩张减少（收缩末期左心室内径，3.59 对 4.08 毫米；P = 0.0188）和较低的心脏重量（133 与 173 毫克；P<0.0001) 横向主动脉收缩后 20 周。组织学和定量聚合酶链反应分析证实心肌细胞肥大减少。在 End.LepR-KO 心脏中，横向主动脉收缩后 STAT3（信号转导和转录激活因子）激活减少，并且 Akt（蛋白激酶 B）和 mTOR（雷帕霉素的哺乳动物靶标）磷酸化减弱。升高的 LC3（微管相关蛋白 1 轻链 3）-I/-II 转化（P = 0.0041）和增加（LC3II 阳性）内皮细胞（P=0.0042) 在 End.LepR-KO 小鼠的带状心脏中表明由于激活的自噬而改善了心脏血管生成。显微镜证实了遗传或小干扰 RNA 介导的 LepR 下调后的自噬体积累。在End.LepR-KO 小鼠的内皮细胞（P <0.0001）和主动脉环（P = 0.0060）中观察到发芽血管生成增强，使用雷帕霉素 mTOR 抑制或使用 3-甲基腺嘌呤抑制自噬后鼠和人内皮发芽血管生成减少. Banded End.LepR-KO小鼠心脏表现出较少的细胞凋亡（P = 0.0218）、炎症（P = 0.0251）和纤维化（P=0.0256）。在心脏纤维化心力衰竭患者的心肌活检中也观察到内皮自噬减少。结论：我们的研究结果表明，内皮瘦素信号通过抑制内皮自噬和促进慢性压力超负荷模型中的内皮功能障碍，导致心脏纤维化和功能恶化。