The orphan receptor NOR 1 participates in isoprenaline‐induced cardiac hypertrophy by regulating PARP ‐1

Background and Purpose The orphan nuclear receptor NOR 1 belongs to the NR4A subfamily of the nuclear hormone receptor superfamily, and is involved in glucose and fat metabolism. However, its potential contribution to cardiovascular diseases remains to be assessed. Here, the roles of NOR 1 in cardiac hypertrophy induced by isoprenaline and the underlying molecular mechanisms were investigated. Experimental Approach NOR 1 was expressed in cardiomyocytes treated with isoprenaline. After NOR 1 overexpression or knockdown in neonatal rat cardiomyocytes, cellular hypertrophy was monitored by measuring cell surface area and the m RNA of hypertrophic biomarkers. Interactions between NOR 1 and PARP ‐1 were investigated by co‐immunoprecipitation. NOR 1 expression and PARP ‐1 activity were measured in rats with cardiac hypertrophy induced by isoprenaline. Key Results Treatment with isoprenaline significantly up‐regulated NOR 1 expression and PARP ‐1 activity both in vivo and in vitro . Specific gene silencing of NOR 1 attenuated isoprenaline‐induced cardiomyocyte hypertrophy, whereas NOR 1 overexpression exacerbated cardiac hypertrophy. We identified a physical interaction between NOR 1 and PARP ‐1, which was enhanced by NOR 1 transfection and thereby led to PARP ‐1 activation. Overexpression of NOR 1, but not C293Y , a NOR 1 mutant lacking the PARP ‐1 binding activity, increased cellular surface area and the m RNA levels of atrial natriuretic factor and brain natriuretic polypeptide, effects blocked by the PARP ‐1 inhibitor 3‐aminobenzamide or si RNA for PARP ‐1. Conclusions and Implications This is the first evidence that NOR 1 was involved in isoprenaline‐induced cardiac hypertrophy. The pro‐hypertrophic effect of NOR 1 can be partly attributed to its regulation of PARP ‐1 enzymic activity.