The nuclear receptor ROR-alpha is a critical myogenic regulator of the cardiomyocyte transcriptome, including the alpha-1A adrenergic receptor

Abstract

AimsWe recently found that the nuclear receptor retinoic acid-related orphan nuclear receptor alpha (ROR) protects against angiotensin II-induced cardiac hypertrophy and promotes cardiomyocyte mitophagy. The underlying molecular basis for these salutary effects remains unclear. MethodsWe used RNA microarrays to profile the cardiac transcriptomes of "staggerer" (RORsg/sg) mice that carry a naturally occurring mutation in the ligand-binding domain of ROR, resulting in a global loss-of-function genetic model. We then used genetic and pharmacologic loss-and-gain of function studies in cultured cardiomyocytes to ascertain whether ROR regulates transcription of Adra1a, the gene that encodes the alpha-1A-adrenergic receptor (1A-AR). ResultsThe absence of functional ROR results in broad transcriptional changes in the heart providing a likely molecular basis for the RORsg/sg cardiac phenotype. In vivo and in vitro studies confirmed that ROR directly regulates Adra1a transcription. This effect is enhanced by hypoxia. ConclusionsCollectively these findings position ROR as a previously unrecognized central regulator of the cardiac myogenic transcriptome and the first recognized transcriptional regulator of Adra1a in cardiomyocytes. Future studies will probe the contribution of ROR-mediated transcriptional regulation of Adra1a to both the response to cardiomyocyte injury and maintenance of circadian biology.