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Novel protective role of the circadian nuclear receptor retinoic acid‐related orphan receptor‐α in diabetic cardiomyopathy
Author(s) -
Zhao Yichao,
Xu Longwei,
Ding Song,
Lin Nan,
Ji Qingqi,
Gao Lingchen,
Su Yuanyuan,
He Ben,
Pu Jun
Publication year - 2017
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12378
Subject(s) - orphan receptor , nuclear receptor , diabetic cardiomyopathy , endocrinology , medicine , retinoic acid receptor , receptor , retinoic acid , circadian rhythm , cardiomyopathy , biology , biochemistry , genetics , heart failure , transcription factor , cell culture , gene
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 ( ROR α), was downregulated in diabetic hearts. By utilizing a mouse line with ROR α disruption, we demonstrated that ROR α deficiency led to significantly augmented diastolic dysfunction and cardiac remodeling induced by diabetes. Microscopic and molecular analyses further indicated that the detrimental effects of ROR α deficiency were associated with aggravated myocardial apoptosis, autophagy dysfunction, and oxidative stress by disrupting antioxidant gene expression. By contrast, restoration of cardiac ROR α levels in transgenic mice significantly improved cardiac functional and structural parameters at 8 weeks after diabetes induction. Consistent with genetic manipulation, pharmacological activation of ROR α by melatonin and SR 1078 (a synthetic agonist) showed beneficial effects against diabetic cardiomyopathy, while the ROR α inhibitor SR 3335 significantly exacerbated cardiac impairments in diabetic mice. Collectively, these findings suggest that cardiac‐targeted manipulation of nuclear melatonin receptor ROR α may hold promise for delaying diabetic cardiomyopathy development.