Novel protective role of the circadian nuclear receptor retinoic acid-related orphan receptor-α in diabetic cardiomyopathy.
Novel protective role of the circadian nuclear receptor retinoic acid-related orphan receptor-α in diabetic cardiomyopathy.
复制标题
昼夜节律核受体视黄酸相关孤儿受体-α 在糖尿病心肌病中的新保护作用。
DOI：
10.1111/jpi.12378
复制
发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Jun Pu
中科院分区：
文献类型：
--
作者：
Yichao Zhao;Longwei Xu;Song Ding;Nan Lin;Qingqi Ji;Lingchen Gao;Yuanyuan Su;Ben He;Jun Pu
糖尿病心肌病是糖尿病患者的主要并发症，在治疗方法较少的情况下，其发病率和死亡率显著增加。此外，抗糖尿病药物报告不一致，甚至不良的心血管作用，这表明重要的是开发新的治疗靶点对糖尿病心肌病。在这里，我们观察到核褪黑激素受体，视黄酸相关孤儿受体-α（RORα），在糖尿病心脏中下调。通过使用RORα破坏的小鼠系，我们证明RORα缺陷导致糖尿病诱导的舒张功能障碍和心脏重构显著增强。显微镜和分子分析进一步表明，RORα缺乏的不利影响与加重心肌细胞凋亡，自噬功能障碍和氧化应激通过破坏抗氧化基因的表达。相比之下，在糖尿病诱导后8周，转基因小鼠心脏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SR 1078（一种合成激动剂）对RORα的药理学激活显示出对糖尿病心肌病的有益作用，而RORα抑制剂SR 3335显著加重了糖尿病小鼠的心脏损伤。总的来说，这些发现表明，心脏靶向操纵核褪黑激素受体RORα可能有希望延缓糖尿病心肌病的发展。
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.