The nuclear receptor ROR-alpha is a putative novel myogenic regulator of the cardiomyocyte transcriptome, including...

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 target genes for this ligand-activated transcriptional coregulator have not been defined in the heart. 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). The absence of functional RORα results in broad transcriptomic changes in the heart, suggesting that transcriptional regulation rather than noncanonical effects of RORα likely underlies the RORα^sg/sg cardiac phenotype. In vivo and in vitro studies confirm that RORα directly regulates Adra1a transcription. This effect is enhanced by hypoxia. Collectively, these findings suggest that RORα may contribute broadly to regulating the cardiac transcriptome and identify RORα as 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 the maintenance of circadian biology.NEW & NOTEWORTHY The transcriptomic landscape of retinoic acid-related orphan nuclear receptor alpha (RORα) in the heart is defined for the first time. It includes key sarcomeric genes and other myogenic transcription factors. RORα is identified as the first bona fide transcriptional regulator of cardiac alpha-1A adrenergic receptor (α1A-AR) abundance, acting through direct binding to the Adra1a promoter to enhance its expression in cardiomyocytes, particularly under hypoxic stress. Cardiac α1A-ARs exhibit synchronous circadian oscillation with RORα, potentially revealing a previously unrecognized rhythmic regulatory axis.