Abstract
Cardiac fibrosis is a maladaptive response to various stresses, characterized by increased interstitial collagen deposition and progressive cardiac dysfunction. The transdifferentiation of fibroblasts into myofibroblasts is an essential process in the pathogenesis of cardiac fibrosis. SIRT3, as a mitochondrial NAD+-dependent histone deacetylase, has been demonstrated beneficial in many cardiovascular diseases. However, the specific mechanism of its protective role in cardiac fibrosis needs to be elucidated further. Here, we determined the role of SIRT3 in cardiac fibrosis by subjecting Sirt3-knockout mice to chronic AngII infusion for four weeks in vivo. In this study, the Sirt3-knockout mice developed more serious cardiac fibrosis compared to wild-type controls. In vitro, primary cardiac fibroblasts from Sirt3-knockout mice transdifferentiated into myofibroblasts spontaneously and this phenotype conversion exaggerated after AngII stimulation. The SIRT3-KO myofibroblasts secret more fibrotic mediators including TGF-β to promote cardiac fibrosis. In addition, the overexpression of SIRT3 by lentivirus transfection attenuated myofibroblasts transdifferentiation. We further demonstrated that SIRT3 directly binds to and deacetylates STAT3 to inhibit its activity. Sequentially the downstream factor, known as NFATc2, showed a reduced expression. Taken together, these results revealed that SIRT3 can protect against cardiac fibrosis by inhibiting myofibroblasts transdifferentiation via the STAT3-NFATc2 signaling pathway.