Micro RNA‐301a‐induced NF‐kB‐p50 activation mediates microRNA‐130b up‐regulation in the failing heart

Abstract

Background Micro RNAs (miRs) regulate gene expression and have been implicated in a number of pathologies including heart failure (HF). miR-130b and 301a belong to a broadly conserved family of miRs whose role in failing hearts is unknown. Methods/Results miRNA analysis of human HF samples revealed a significant increase in the expression of both miR-130b and miR-301a. Evaluation of miR-301a mRNA targets identified Tax-1 binding protein 1 (TAX1BP1) as one of its potential targets. TAX1BP1, by inhibiting A20 enzyme inhibits NF-κB activation. Analysis of miR-130b promoter identified a putative NF-κB binding site. We hypothesized that miR-301a regulates the expression of miR-130b. Overexpression of miR-301a resulted in a significant increase in NF-kB-reporter activity and downregulated TAX1BP1 protein expression. miR-301a overexpression primarily induced NF-κB-p50 translocation. Overexpression of miR-301a, however, did not induce miR-130b expression in rat myoblast H9c2 cells that do not express NF-κB p50. This effect was restored upon overexpression of exogenous NF-κB-p50 but not NF-κB-p65 suggesting that miR-301a-induced NF-κB p50 activation mediates the up-regulation of miR-130b. Conclusions Evaluation of miRNA targets specific to miR-130b could identify inhibitory NF-κB p50-specific responses in failing hearts and therefore would have important therapeutic implications. Financial support: NIH, VA, AHA.