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

Abstract Aims We recently found that the nuclear receptor retinoic acid-related orphan nuclear receptor alpha (RORα) protects against angiotensin II-induced cardiac hypertrophy and promotes cardiomyocyte mitophagy. The underlying molecular basis for these salutary effects remains unclear. Methods We used RNA microarrays to profile the cardiac transcriptomes of “staggerer” (RORα sg/sg ) mice that carry a naturally occurring mutation in the ligand-binding domain of RORα, 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 RORα regulates transcription of Adra1a , the gene that encodes the alpha-1A-adrenergic receptor (α1A-AR). Results The absence of functional RORα results in broad transcriptional changes in the heart providing a likely molecular basis for the RORα sg/sg cardiac phenotype. In vivo and in vitro studies confirmed that RORα directly regulates Adra1a transcription. This effect is enhanced by hypoxia. Conclusions Collectively these findings position RORα 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 RORα-mediated transcriptional regulation of Adra1a to both the response to cardiomyocyte injury and maintenance of circadian biology.