Targeting ACTG1 alleviates isoproterenol-induced cardiac injury by regulating endothelial-to-mesenchymal transition

The pathological mechanisms underlying cardiac fibrosis after isoproterenol (ISO)-induced cardiac injury remain poorly understood. Additionally, the biological function of ACTG1 in cardiovascular diseases has not been fully elucidated. This study aims to explore the role of ACTG1 and its regulatory mechanism in ISO-triggered cardiac injury and fibrosis. We established ISO-induced cardiomyocyte injury models and TGF-β1-stimulated vascular endothelial cell-endothelial-to-mesenchymal transition (EndoMT) models in vitro, and then evaluated the effects of ACTG1 silencing on cardiomyocyte functions and EndoMT progression in vascular endothelial cells. Conditioned medium (CM) and a TGF-β1 neutralizing antibody were applied to explore the paracrine crosstalk between cardiomyocytes and vascular endothelial cells. In vivo, an ISO-induced mouse model of cardiac injury was constructed to verify the regulatory effects of ACTG1 silencing on myocardial injury, fibrosis, inflammation, and EndoMT. The in vitro results demonstrated that ISO treatment upregulated ACTG1 expression at both the mRNA and protein levels in cardiomyocytes. Moreover, ACTG1 silencing attenuated ISO-induced cardiomyocyte injury and partially suppressed TGF-β1-mediated EndoMT in vascular endothelial cells. Further mechanistic experiments revealed that ACTG1 silencing in ISO-induced cardiomyocytes hindered EndoMT progression in vascular endothelial cells. TGF-β1 neutralization assays further confirmed that TGF-β1 acted as a key paracrine mediator linking cardiomyocyte activation to endothelial EndoMT. In addition, the silencing of ACTG1 in vivo attenuated myocardial injury, reduced collagen deposition, improved cardiac function, and downregulated the expression of EndoMT-related proteins in ISO-treated mice. ACTG1 exacerbated ISO-induced cardiomyocyte injury and facilitated EndoMT to promote cardiac injury and fibrosis, supporting ACTG1 as a promising therapeutic target for the treatment of cardiac injury.