Novel protective role of the circadian nuclear receptor retinoic acid‐related orphan receptor‐α in diabetic cardiomyopathy

Abstract

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.

Melatonin prevents Drp1‐mediated mitochondrial fission in diabetic hearts through SIRT1‐PGC1α pathway

“…Similar to the cardioprotective effects of mdivi‐1, we found that melatonin prevented Drp1‐mediated mitochondrial fission and alleviated cardiac dysfunction in diabetic mice. Previous studies have reported that melatonin alleviated cardiac dysfunction via activation of retinoic acid‐related orphan receptor‐α and regulation of autophagy in diabetic hearts . The present work indicates that melatonin‐inhibited mitochondrial fission may be a novel mechanism underlying its cardioprotective effect in diabetes.…”

“…Melatonin was injected at 9:00 am every morning when serum melatonin level was relatively low. The dosage of melatonin or mdivi‐1 treatment was chosen based on previous studies about the effect of melatonin or mdivi‐1 on diabetic complications . At the end of the experiments (12 weeks after the first injection of STZ), hearts were collected for mitochondrial dynamics, apoptosis, ROS generation, and Western blot analyses.…”

“…Melatonin, chemically N‐acetyl‐5‐methoxytryptamine, has been proved to exert its protective properties in a variety of cardiovascular diseases . Recent studies have reported that melatonin has the ability to protect against diabetes‐induced cardiac dysfunction . Our previous study demonstrated that melatonin alleviated posttraumatic myocardial injury and cardiac dysfunction.…”

Melatonin protects against diabetic cardiomyopathy through Mst1/Sirt3 signaling

“…Melatonin exerts free radical scavenging and antioxidant actions, thereby protecting against cardiovascular injuries . Accumulating studies indicate that melatonin have protective effects against DCM . Our previous study demonstrated that melatonin alleviated left ventricular remodeling and cardiac dysfunction after myocardial infarction .…”

The orphan nuclear receptor RORα is a potential endogenous protector in renal ischemia/ reperfusion injury

“…Regarding the signaling pathways by which RORα regulates epithelial apoptosis in I/R‐induced AKI, previous studies have reported that the epithelial apoptotic cascade associated with AKI initially comprises mitochondrial deformation, endoplasmic reticulum stress, and the activation of death receptors, followed by the activation of specific caspases and cell death (19). RORα has been demonstrated to suppress myocardial apoptosis by ameliorating mitochondrial dysfunction (mitochondrial swelling) and caspase‐9 activation and down‐regulating endoplasmic reticulum stress markers (11,41). Consistent with these results, our results suggest that the antiapoptotic effects of the RORα pathway in I/R‐induced AKI are associated with the inhibition of mitochondrial and endoplasmic reticulum stress, a phenomenon reflected by decreases in the Bax/Bcl‐2 ratio and the inhibition of caspase‐9 and ‐12 expression.…”