The nuclear receptor RORα protects against angiotensin II-induced cardiac hypertrophy and heart failure.

The nuclear receptor retinoic acid-related orphan receptor-alpha (ROR alpha) regulates numerous critical biological processes, including central nervous system development, lymphocyte differentiation, and lipid metabolism. ROR alpha has been recently identified in the heart, but very little is known about its role in cardiac physiology. We sought to determine whether ROR alpha regulates myocardial hypertrophy and cardiomyocyte survival in the context of angiotensin II (ANG II) stimulation. For in vivo characterization of the function of ROR alpha in the context of pathological cardiac hypertrophy and heart failure, we used the "staggerer" (ROR alpha(sg/sg)) mouse, which harbors a germline mutation encoding a truncated and globally nonfunctional ROR alpha. ROR alpha(sg/sg) and wild-type littermate mice were infused with ANG II or vehicle for 14 days. For in vitro experiments, we overexpressed or silenced ROR alpha in neonatal rat ventricular myocytes (NRVMs) and human cardiac fibroblasts exposed to ANG II. ROR alpha(sg/sg) mice developed exaggerated myocardial hypertrophy and contractile dysfunction after ANG II treatment. In vitro gain-and loss-of-function experiments were consistent with the discovery that ROR alpha inhibits ANG II-induced pathological hypertrophy and cardiomyocyte death in vivo. ROR alpha directly repressed IL-6 transcription. Loss of ROR alpha function led to enhanced IL-6 expression, proinflammatory STAT3 activation (phopho-STAT3 Tyr(705)), and decreased mitochondrial number and function, oxidative stress, hypertrophy, and death of cardiomyocytes upon ANG II exposure. ROR alpha was less abundant in failing compared with nonfailing human heart tissue. In conclusion, ROR alpha protects against ANG II-mediated pathological hypertrophy and heart failure by suppressing the IL-6-STAT3 pathway and enhancing mitochondrial function. NEW & NOTEWORTHY Mice lacking retinoic acid-related orphan receptor-alpha (ROR alpha) develop exaggerated cardiac hypertrophy after angiotensin II infusion. Loss of ROR alpha leads to enhanced IL-6 expression and NF-kappa B nuclear translocation. ROR alpha maintains mitochondrial function and reduces oxidative stress after angiotensin II. The abundance of ROR alpha is reduced in failing mouse and human hearts.