Abstract
Cardiac fibrosis is a hallmark of numerous chronic cardiovascular diseases that leads to heart failure. However, there is no validated therapy for it. Dysregulation of microRNAs has been confirmed to be involved in cardiac fibrosis development. However, the regulatory network was not well explored. This study was the first to highlight the role and molecular mechanism of miR-409-3p in cardiac fibrosis. We found that miR-409-3p was consistently increased in three fibrotic models, including heart tissues of postmyocardial infarction (MI) mice and neonatal rat cardiac fibroblasts treated with angiotensin II (Ang II) or transforming growth factor-β (TGF-β). Furthermore, myocardial infarction surgery-induced cardiac fibrosis and dysfunction were attenuated by systemic delivery of miR-409-3p antagomir. Notably, transfection with miR-409-3p mimics promoted the proliferation of cardiac fibroblasts and fibroblast-to-myofibroblast differentiation, accompanied by upregulated expression of Col1a1, Col3a1, and α-SMA. On the contrary, the miR-409-3p inhibitor exhibited the opposite effect. Following this, we verified Gpd1 as a direct target of miR-409-3p. Gpd1 siRNA abolished the antifibrotic effect of miR-409-3p inhibitor in neonatal rat cardiac fibroblasts, suggesting that miR-409-3p promotes cardiac fibrosis at least partially through Gpd1. Moreover, GATA2 was identified as a cardiac fibrosis-associated upstream positive transcription factor of miR-409-3p. Finally, these findings suggest that modulating miR-409-3p could be a potential therapeutic method for cardiac fibrosis.