sST2: A Bridge Between Sirt1/p53/p21 Signal-Induced Senescence and TGF-β1/Smad2/3 Regulation of Cardiac Fibrosis in Mouse Viral Myocarditis

Soluble interleukin 1 receptor-like 1 (sST2) is a novel predictor of poor outcomes, which is involved in inflammatory response and fibrosis of myocarditis. Cellular senescence is a state of irreversible cell cycle arrest. Studies have shown that senescence of myofibroblasts can limit or reduce cardiac fibrosis. However, the molecular mechanism of sST2 regulating cellular senescence is still unclear. Here, we investigate the role of sST2 on cellular senescence in cardiac fibrosis. Our results found that sST2 was upregulated in coxsackievirus group B type 3 (CVB3)-induced viral myocarditis (VMC), which correlated with the expression of senescence markers. In vitro, sST2 activated TGFβ signaling through the phosphorylation of the SMAD complex to induce mouse cardiac fibroblast (MCF) activation and inhibit cellular senescence by the Sirt1/p53/p21 signaling pathway. In vivo, anti-ST2 mAb attenuated CVB3-induced cardiac fibrosis. Our findings elucidate a crucial mechanism underlying through which sST2 inhibits cellular senescence and regulates MCF activation, providing a potential treatment strategy for cardiac fibrosis.