Abstract
Cardiac hypertrophy contributes to heart failure and is pathogenically modulated by a network of signaling cascades including Wnt/β-catenin signaling pathway. miRNAs have been widely demonstrated to regulate gene expression in heart development. miR-128 was routinely found as a brain-enriched gene and has been functionally associated with regulation of cardiac function. However, its role and molecular mechanisms that regulate cardiac hypertrophy remain largely unclear. Adeno-associated virus serotype 9 (AAV9)-mediated constructs with miR-128 or anti-miR-128 were generated and delivered to overexpression or blockade of miR-128 in vivo followed by HF induction with isoproterenol (ISO) or transverse aortic constriction (TAC). Cardiac dysfunction and hypertrophy, coupled with involved gene and protein level, were then assessed. Our data found that miR-128, Wnt1, and β-catenin expressions were upregulated in both patients and mice model with HF. Interference with miR-128 reduces Wnt1/β-catenin expression in mouse failing hearts and ameliorates heart dysfunctional properties. We identified miR-128 directly targets to Axin1, an inhibitor of Wnt/β-catenin signaling, and suppresses its inhibition on Wnt1/β-catenin. Our study provides evidence indicating miR-128 as an inducer of HF and cardiac hypertrophy by enhancing Wnt1/β-catenin in an Axin1-dependent nature. We thus suggest miR-128 has potential value in the treatment of heart failure.