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

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 target genes for this ligand-activated transcriptional co-regulator have not been defined in the heart. 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 transcriptomic changes in the heart, suggesting that transcriptional regulation rather than non-canonical effects of RORα likely underlie 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. Conclusions: 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 maintenance of circadian biology.