| First Author | Beak JY | Year | 2019 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 316 |
| Issue | 1 | Pages | H186-H200 |
| PubMed ID | 30387679 | Mgi Jnum | J:269589 |
| Mgi Id | MGI:6273668 | Doi | 10.1152/ajpheart.00531.2018 |
| Citation | Beak JY, et al. (2019) The nuclear receptor RORalpha protects against angiotensin II-induced cardiac hypertrophy and heart failure. Am J Physiol Heart Circ Physiol 316(1):H186-H200 |
| abstractText | The nuclear receptor retinoic acid-related orphan receptor-alpha (RORalpha) regulates numerous critical biological processes, including central nervous system development, lymphocyte differentiation, and lipid metabolism. RORalpha has been recently identified in the heart, but very little is known about its role in cardiac physiology. We sought to determine whether RORalpha regulates myocardial hypertrophy and cardiomyocyte survival in the context of angiotensin II (ANG II) stimulation. For in vivo characterization of the function of RORalpha in the context of pathological cardiac hypertrophy and heart failure, we used the "staggerer" (RORalpha(sg/sg)) mouse, which harbors a germline mutation encoding a truncated and globally nonfunctional RORalpha. RORalpha(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 RORalpha in neonatal rat ventricular myocytes (NRVMs) and human cardiac fibroblasts exposed to ANG II. RORalpha(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 RORalpha inhibits ANG II-induced pathological hypertrophy and cardiomyocyte death in vivo. RORalpha directly repressed IL-6 transcription. Loss of RORalpha 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. RORalpha was less abundant in failing compared with nonfailing human heart tissue. In conclusion, RORalpha 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 (RORalpha) develop exaggerated cardiac hypertrophy after angiotensin II infusion. Loss of RORalpha leads to enhanced IL-6 expression and NF-kappaB nuclear translocation. RORalpha maintains mitochondrial function and reduces oxidative stress after angiotensin II. The abundance of RORalpha is reduced in failing mouse and human hearts. |
