Objectives: The RAR-related orphan receptors (RORs) are members of the nuclear receptor superfamily that play a pivotal role in many physiological processes, including regulation of the circadian rhythm, development, metabolism and immune function. Three different but highly homologous ROR isoforms, ROR-α, -β, and -γ, have been discovered separately. However, the functional roles of RORs in the heart have never been investigated. We investigate the role of RORs in the pathophysiology of acute myocardial ischemia/ reperfusion (MI/R) injury.
Methods and Results: The endogenous RORα, but not RORβ or RORγ, was significantly upregulated after MI/R. Synthetic ROR agonists SR1078 and SR3335 reduced myocardial infarction and improved contractile function after MI/R. Mechanistically, ROR activation inhibited endoplasmic reticulum (ER) stress, attenuated mitochondrial impairment, reduced cardiomyocyte apoptosis, and inhibited MI/R-induced autophagy dysfunction. Moreover, ROR activation inhibited MI/R-induced oxidative stress and nitrative stress. The aforementioned cardioprotective effects of ROR agonists were impaired in the setting of cardiac-specific gene silencing of RORα, but not RORβ or RORγ subtype. In contrast, adenovirus-mediated cardiac RORα overexpression, but not RORβ or RORγ overexpression, decreased myocardial infarct size and improved cardiac function through attenuating oxidative/nitrative stress and inhibiting ER stress, mitochondrial impairment, and autophagy dysfunction. Finally, RORαsg/sg mice (loss-of-function mutation in RORα), but not RORβ-null or RORγ-null mice, increased MI/R injury (greater apoptosis, larger infarct size, and poor cardiac function), exacerbated MI/R-induced oxidative/nitrative stress, and aggravated endoplasmic-reticulum stress, mitochondrial dysfunction, and autophagy dysfunction.
Conclusion: Our study provides the first direct evidence that RORα acts as a novel endogenous cardioprotective receptor against myocardial injury. RORα, but not RORβ or RORγ, is a novel cardiac protective receptor against MI/R injury, supporting for the drug development strategies specifically targeting RORα for the treatment of ischemic heart disease.