Kallistatin/Serpina3c inhibits cardiac fibrosis after myocardial infarction by regulating glycolysis via Nr4a1 activation

Abstract

BackgroundFibrotic remodeling is an essential aspect of heart failure. Human kallistatin (KS, mouse Serpina3c homologs) inhibits fibrosis after myocardial infarction (MI) but the specific underlying mechanism is unknown. MethodsA total of 40 heart failure patients (HFPs) were enrolled and their plasma KS was measured using ELISA. Serpina3c−/− and C57BL/6 mice were used to construct the MI model. TGF-β1 or a hypoxic condition was established to interfere with the functioning of cardiac fibroblasts (CFs). RNA-seq was performed to assess the effect of Serpina3c on the transcriptome. FindingsThe levels of KS were used as a predictor of readmission among the HFPs. Serpina3c expression decreased in MI hearts and CFs. Serpina3c−/− led to the aggravation of MI fibrosis, and increased the proliferation of CFs. The overexpression of Serpina3c in CFs had the opposite effect. Glycolysis-related genes were significantly increased in Serpina3c−/− group by RNA-seq. Enolase (ENO1), which is a key enzyme in glycolysis, increased most significantly. Inhibition of ENO1 could antagonize the promotion of Serpina3c−/− on the proliferation of CFs. Co-IP was performed to verify the interaction between Serpina3c and Nr4a1. Serpina3c−/− inhibited the acetylation of Nr4a1 and increased the degradation of Nr4a1. Activation of Nr4a1 could negatively regulate the expression of ENO1 and inhibited the proliferation of Serpina3c−/− CFs in Serpina3c−/− MI mice. InterpretationSerpina3c inhibits the transcriptional activation of ENO1 by regulating the acetylation of Nr4a1, thereby reducing the fibrosis after MI by inhibiting glycolysis. Serpina3c is a potential target for prevention and treatment of heart failure after MI.