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

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. A total of 40 heart failure patients (HFPs) were enrolled and their plasma KS was measure...

Full description

Saved in:
Bibliographic Details
Published in:Biochimica et biophysica acta. Molecular basis of disease 2022-09, Vol.1868 (9), p.166441-166441, Article 166441
Main Authors: Ji, Jing-jing, Qian, Ling-lin, Zhu, Yi, Jiang, Yu, Guo, Jia-qi, Wu, Ya, Yang, Zi-wei, Yao, Yu-yu, Ma, Gen-shan
Format: Article
Language:English
Subjects:
Fibrosis
Glycolysis
Myocardial infarction
Nr4a1
Serpina3c
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. 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. 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. 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. [Display omitted] •KS/Serpina3c was down-regulated after MI. Knockout of Serpina3c led to aggravation of cardiac fibrosis.•KS/Serpina3c inhibited the excessive activation of glycolysis and the proliferation and differentiation of fibroblasts.•KS/Serpina3c inhibited the transcription of ENO1, a key enzyme of glycolysis, through Nr4a1 acetylation.
ISSN:0925-4439
1879-260X
DOI:10.1016/j.bbadis.2022.166441