The nuclear melatonin receptor RORα is a novel endogenous defender against myocardial ischemia/reperfusion injury

Abstract Circadian rhythm disruption or decrease in levels of circadian hormones such as melatonin increases ischemic heart disease risk. The nuclear melatonin receptors ROR s are pivotally involved in circadian rhythm regulation and melatonin effects mediation. However, the functional roles of ROR s in the heart have never been investigated and were therefore the subject of this study on myocardial ischemia/reperfusion ( MI /R) injury pathogenesis. ROR α and ROR γ subtypes were detected in the adult mouse heart, and ROR α but not ROR γ was downregulated after MI /R. To determine the pathological consequence of MI /R‐induced reduction of ROR α , we subjected ROR α ‐deficient staggerer mice and wild‐type ( WT ) littermates to MI /R injury, resulting in significantly increased myocardial infarct size, myocardial apoptosis and exacerbated contractile dysfunction in the former. Mechanistically, ROR α deficiency promoted MI /R‐induced endoplasmic reticulum stress, mitochondrial impairments, and autophagy dysfunction. Moreover, ROR α deficiency augmented MI /R‐induced oxidative/nitrative stress. Given the emerging evidence of ROR α as an essential melatonin effects mediator, we further investigated the ROR α roles in melatonin‐exerted cardioprotection, in particular against MI /R injury, which was significantly attenuated in ROR α ‐deficient mice, but negligibly affected by cardiac‐specific silencing of ROR γ . Finally, to determine cell type‐specific effects of ROR α , we generated mice with cardiomyocyte‐specific ROR α overexpression and they were less vulnerable to MI /R injury. In summary, our study provides the first direct evidence that the nuclear melatonin receptor ROR α is a novel endogenous protective receptor against MI /R injury and an important mediator of melatonin‐exerted cardioprotection; melatonin‐ ROR α axis signaling thus appears important in protection against ischemic heart injury.