miR-424/322 attenuates cardiac remodeling by modulating the nuclear factor-activated T-cell 3/furin pathway.

Background: Cardiac remodeling is implicated in numerous physiologic and pathologic conditions, including scar formation, heart failure, and cardiac arrhythmias. Nuclear factor-activated T-cell cytoplasmic (NFATc) is a crucial transcription factor that regulates cardiac remodeling. MicroRNA (miR)-424/322 has pathophysiological roles in the cardiovascular and respiratory systems by modulating hypoxia and inflammatory pathways. The role of miR-424/322 in regulating cardiac remodeling is under investigation. We identified several cardiac hypertrophy and fibrosis-related molecules as putative targets of miR-424/322. We propose that miR-424/322 could have crucial roles in cardiac remodeling by modulating several key molecules for cardiac fibrosis and hypertrophy.

Methods: Human cardiac fibroblasts (HCFs) and a myogenic cell line H9c2 cells were used for in vitro experiments. A murine model of angiotensin II (AngII)-induced cardiac remodeling was used to assess the roles of miR-322 on cardiac hypertrophy and fibrosis in vivo. Immunoblotting, immunofluorescence, real-time polymerase chain reaction and cell proliferation, Sirius Red, and dual-luciferase reporter assays were used to decipher the molecular mechanism.

Results: We found that miR-322 knockout mice were susceptible to AngII-induced cardiac fibrosis and hypertrophy in vivo. Administration of miR-424/322 inhibitors aggravated AngII-induced overexpression of NFATc3, furin, natriuretic peptides and collagen 1A1 in H9c2 cells and HCFs. miR-424/322 mimics reversed the AngII-induced fibrosis, hypertrophy, and proliferation by targeting NFATc3 and furin in vitro. miR-424/322 could be transactivated by NFATc3. Exogenous miR-322 ameliorated AngII-induced hypertrophy and cardiac fibrosis in vivo.

Conclusions: The NFATc3/miR-424/322/furin axis is crucial for developing cardiac remodeling, and exogenous miR-322 mimics could have therapeutic potential in cardiac remodeling.