sST2: A bridge between Sirt1/p53/p21 signal-induced senescence and TGF-β1/Smad2/3 regulation of cardiac fibrosis in mice viral myocarditis

Abstract

Soluble interleukin 1 receptor-like 1 (sST2) is a novel predictor of poor outcomes, which is involved in inflammatory response and fibrosis of myocarditis. Cardiac fibrosis is a major cause of cardiovascular disease. Cellular senescence is a state of irreversible cell cycle arrest and studies have shown that senescence of myofibroblasts can limit or reduce myocardial fibrosis. Previous studies show that cellular senescence is associated with the progress of myocarditis, and cardiac fibroblasts is closely related to cardiac fibrosis. Therefore, we investigated the role of sST2 on senescence and fibrosis in mice cardiac fibroblasts (MCF). Meanwhile, its pathological role in mice viral myocarditis (VMC) was also investigated. In vitro experiments revealed that sST2 is beneficial to activate MCF by TGF-β1/Smad2/3 signaling and inhibit cell senescence by Sirt1/P53/P21 signaling pathway. CVB3-infected mice exhibited an increased deposition of collagen in the heart and decreased MCF senescence compared to WT mice while these pathological effects are reversed by anti-ST2 mAb. In addition, we found that inhibiting the senescence of MCF is beneficial to cardiac fibrosis and this effect is achieved by paracrine action. The present study reveals a new pathogenic pathway, sST2, which leads to cardiac fibrosis of VMC by inhibiting MCF senescence.