Targeting SYK with miR-512-3p provides therapeutic potential in myocardial fibrosis.

Myocardial fibrosis is a key pathological process in cardiovascular diseases. The activation of myocardial fibroblasts has been shown to be regulated by several signalling pathways, including Ang II signalling pathway. This study aimed to investigate the role of SYK (spleen tyrosine kinase) in myocardial fibrosis and explore its upstream regulator targeting SYK expression. In an isoproterenol (ISO)-induced myocardial fibrosis murine model, SYK was highly expressed in activated myocardial fibroblasts and colocalized with α-SMA. In vitro, Ang II stimulation increased the levels of SYK and its phosphorylated form, promoting fibroblast activation and ECM protein secretion. SYK knockdown effectively inhibited fibroblast activation in HL-1 cells. Bioinformatics analysis and functional screening identified a novel modulator, miR-512-3p, which can suppress the expression of SYK. In vitro, miR-512-3p inhibited fibroblast activation by targeting SYK, reducing fibrosis and cell proliferation. In vivo, miR-512-3p treatment significantly improved cardiac function, as shown by increased left ventricular ejection fraction and fractional shortening values. Additionally, miR-512-3p attenuated myocardial remodelling, with reductions in the left ventricular posterior wall diameter and diastolic left ventricular anterior wall diameter. These results provide strong in vivo evidences that miR-512-3p exhibits antifibrotic effects and protects against cardiac dysfunction and remodelling, suggesting a promising therapeutic strategy for treating myocardial fibrosis.