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

  • Biochim Biophys Acta Mol Basis Dis. 2022 Sep 1;1868(9):166441. doi: 10.1016/j.bbadis.2022.166441.
Jing-Jing Ji  1 ,  Ling-Lin Qian  1 ,  Yi Zhu  1 ,  Yu Jiang  1 ,  Jia-Qi Guo  1 ,  Ya Wu  1 ,  Zi-Wei Yang  1 ,  Yu-Yu Yao  2 ,  Gen-Shan Ma  3
Affiliations
  • 1. Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210009, China.
  • 2. Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210009, China. Electronic address: [email protected].
  • 3. Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210009, China. Electronic address: [email protected].
PMID: 35577178 DOI: 10.1016/j.bbadis.2022.166441
Abstract

Background: Fibrotic 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.

Methods: A 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.

Findings: The 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.

Interpretation: Serpina3c 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.

Keywords
Fibrosis; Glycolysis; Myocardial infarction; Nr4a1; Serpina3c.
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