Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
J Pineal Res. 2017 Apr;62(3). doi: 10.1111/jpi.12378. Epub 2017 Feb 22.
Diabetic cardiomyopathy is a major complication that significantly contributes to morbidity and mortality in diabetics with few therapies. Moreover, antidiabetic drugs reported inconsistent or even adverse cardiovascular effects, suggesting that it is important to exploit novel therapeutic targets against diabetic cardiomyopathy. Here, we observed that the nuclear melatonin receptor, the retinoic acid-related orphan receptor-α (RORα), was downregulated in diabetic hearts. By utilizing a mouse line with RORα disruption, we demonstrated that RORα deficiency led to significantly augmented diastolic dysfunction and cardiac remodeling induced by diabetes. Microscopic and molecular analyses further indicated that the detrimental effects of RORα deficiency were associated with aggravated myocardial apoptosis, autophagy dysfunction, and oxidative stress by disrupting antioxidant gene expression. By contrast, restoration of cardiac RORα levels in transgenic mice significantly improved cardiac functional and structural parameters at 8 weeks after diabetes induction. Consistent with genetic manipulation, pharmacological activation of RORα by melatonin and SR1078 (a synthetic agonist) showed beneficial effects against diabetic cardiomyopathy, while the RORα inhibitor SR3335 significantly exacerbated cardiac impairments in diabetic mice. Collectively, these findings suggest that cardiac-targeted manipulation of nuclear melatonin receptor RORα may hold promise for delaying diabetic cardiomyopathy development.
糖尿病性心肌病是一种主要并发症，它会显著增加糖尿病患者的发病率和死亡率，但目前的治疗方法却很少。此外，抗糖尿病药物的报告显示出不一致甚至不良的心血管作用，这表明开发针对糖尿病性心肌病的新型治疗靶点非常重要。在这里，我们观察到核褪黑素受体、视黄酸相关孤儿受体-α（RORα）在糖尿病心脏中下调。通过利用 RORα 敲除的小鼠品系，我们证明 RORα 缺乏会导致糖尿病引起的舒张功能障碍和心脏重构显著增加。显微镜和分子分析进一步表明，RORα 缺乏的有害影响与抗氧化基因表达的破坏有关，导致心肌细胞凋亡、自噬功能障碍和氧化应激加重。相比之下，在糖尿病诱导 8 周后，转基因小鼠心脏中 RORα 水平的恢复显著改善了心脏功能和结构参数。与遗传操作一致，褪黑素和 SR1078（一种合成激动剂）对 RORα 的药理学激活对糖尿病性心肌病具有有益作用，而 RORα 抑制剂 SR3335 则显著加重了糖尿病小鼠的心脏损伤。总之，这些发现表明，针对核褪黑素受体 RORα 的心脏靶向操作可能有望延缓糖尿病性心肌病的发展。
