Abstract 3555: Nf-kb-dependent Induction Of Microrna-146 Downregulates Erbb4 And May Be Involved In The Deterioration Of Cardiomyocyte Survival
MicroRNAs (miRNAs) are small, non-protein-coding RNAs that recognize target sequences of imperfect complementarities in cognate mRNAs and inhibit protein translation. In mammals, miRNAs have been associated with diverse biological processes, such as cell differentiation, cancer, and viral infection. To examine the potential involvement of miRNAs in the regulation of cellular responses in heart failure, we first performed a miRNA microarray analysis in the heart of Dahl salt-sensitive rats, in which systemic hypertension causes compensated concentric left ventricular hypertrophy (LVH) at the age of 11 weeks, followed by congestive heart failure (CHF) at 17 weeks. We found that the expression of miR-146 was upregulated at both the LVH and CHF stages. Promoter analysis of miR-146 indicated that there are three potential binding sites of NF-kB upstream of miR-146 and activation of NF-kB induced the expression of miR-146. The computational miRNA target prediction algorithm showed that ErbB4 is one of the targets of miR-146. We confirmed that miR-146 targets the ErbB4 3′UTR by assays for a reporter (luciferase) that expressed the miR binding sites of the ErbB4 3′ UTR. Overexpression of miR-146 reduced the expression of ErbB4 and suppressed the phosphorylation of Akt and Erk, which are downstream targets of ErbB4. MiR-146 also decreased the survival rate after stimulation with H2O2. To study the loss of miR-146 function, we constructed ‘decoy’ genes, which had 3 or 6 tandem complementary sequences of miR-146 at the 3′UTR of luciferase gene under the control of CMV promoter. When miR-146 ‘decoy’ genes were introduced into cardiac myocytes, the cardiomyocyte survival after H2O2 treatment improved. Moreover, NF-κB phosphorylation and ErbB4 downregulation was observed in LVH and CHF stages in Dahl salt-sensitive rats. Therefore, the upregulation of miR-146 in LVH and CHF may be involved in the deterioration of cardiac function, which suggests that its regulation is a potential target in heart failure therapy.