Interleukin enhancement binding factor 3 inhibits cardiac hypertrophy by targeting asymmetric dimethylarginine-nitric oxide.

ABSTRACT

Persistent cardiac hypertrophy eventually leads to deterioration of heart function and changes to normal morphology. Decreased nitric oxide (NO) production plays a critical role in modulating cardiac hypertrophy. Interleukin enhancement binding factor 3 (ILF3), a member of the double-stranded RNA-binding protein family, is known to regulate the transcription and stability of mRNA. Therefore, the major aim of the present study was to determine the role of ILF3 in reduction of NO production in cardiac hypertrophy. Cardiac hypertrophy models of neonatal rat cardiomyocytes (NRCMs) and adult rats were induced by angiotensin II (Ang II) in this study. First, it was found that ILF3 expression, NO production, and nitric oxide synthase (NOS) activity was decreased in cultured cardiomyocytes and adult rats treated with Ang II, compared with NRCMs treated with vehicle and rats treated with saline infusion, respectively. These effects induced by Ang II were significantly exacerbated by specific ILF3 knockdown. Moreover, the level of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, was increased significantly in the Ang II-induced hypertrophic NRCMs and adult rats. Additionally, decreased protein expression and mRNA level of dimethylarginine dimethylaminohydrolases 1 (DDAH1, which degrades ADMA) were observed. Furthermore, specific ILF3 knockdown further aggravated these effects, but didn't reduce the expression level of NOS isoforms. In conclusion, our data show that ADMA accumulation-mediated decrease in NO production plays an important role in cardiomyocyte remodeling, which may be associated with ILF3-mediated DDAH1 reduction.