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Updated: Jun 15, 2025
An Experimental Model of Myocardial Infarction for Studying Cardiac Repair and Remodeling in Knockout Mice
Published on: July 14, 2023
KIAA1199/CEMIP knockdown attenuates cardiac remodeling post myocardial infarction by activating TSP4 pathway in mice
Yafang Zha1, Xueyang Luo2, Zhuowang Ge3
1Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, China.
Insights
CEMIP promotes cardiac fibroblast activation and fibrosis post-myocardial infarction (MI). Reducing CEMIP levels improves cardiac function and reduces fibrosis, suggesting CEMIP as a therapeutic target for cardiac remodeling.
Area of Science:
- Cardiovascular Biology
- Fibrosis Research
- Molecular Mechanisms of Disease
Background:
- Cardiac fibroblast (CF) activation drives adverse cardiac remodeling after myocardial infarction (MI).
- CEMIP, an enzyme degrading hyaluronic acid (HA), is implicated in pulmonary fibroblast activation.
- The role of CEMIP in cardiac remodeling post-MI is largely unknown.
Purpose of the Study:
- To investigate the role and mechanism of CEMIP in cardiac remodeling following MI.
- To determine if CEMIP contributes to cardiac fibroblast activation and fibrosis.
- To explore CEMIP as a potential therapeutic target for post-MI cardiac fibrosis.
Main Methods:
- RNA sequencing (RNA-seq) on mouse cardiac tissue and primary CFs.
- In vivo CEMIP knockdown using adeno-associated virus serotype 9 (AAV9).
- Immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (co-IP) to identify protein interactions and mechanisms.
Main Results:
- CEMIP was significantly upregulated in fibrotic heart tissue post-MI.
- CEMIP promoted cardiac fibroblast activation in vitro.
- CEMIP knockdown reduced cardiac fibrosis and improved cardiac function post-MI.
- CEMIP interacts with TSP4 and promotes its lysosomal degradation via ACTN4, activating FAK signaling.
Conclusions:
- CEMIP plays a significant role in cardiac remodeling and fibrosis post-MI.
- CEMIP is a potential novel therapeutic target for treating cardiac fibrosis.
- Targeting CEMIP may offer a new strategy for managing adverse cardiac remodeling after MI.
Background:
Excessive activation of cardiac fibroblasts (CFs) significantly contributes to adverse cardiac remodeling post-myocardial infarction (MI). CEMIP, initially recognized as an enzyme involved in hyaluronic acid (HA) degradation, has also been implicated in the activation of pulmonary fibroblasts. Nevertheless, the role and mechanism of CEMIP in adverse cardiac remodeling following MI remain largely unexplored.
Materials And Methods:
RNA sequencing (RNA-seq) was performed on cardiac tissue harvested from the infarct/peri-infarct region of mice 28 days post-MI. RNA-seq was conducted on primary cardiac fibroblasts (CFs) transfected with adenovirus overexpressing CEMIP. Adeno-associated virus serotype 9 (AAV9) was engineered for in vivo CEMIP knockdown to elucidate its impact on cardiac remodeling. Immunoprecipitation coupled with mass spectrometry (IP-MS) and co-immunoprecipitation (co-IP) were employed to elucidate the mechanism by which CEMIP affected cardiac remodeling.
Key Findings:
RNA-seq of fibrotic heart tissue at day 28 post-MI revealed a significant upregulation of CEMIP. In vitro, CEMIP facilitated the activation of cardiac fibroblasts. In vivo, knockdown of CEMIP markedly reduced cardiac fibrosis and improved cardiac function post-MI. IP-MS and co-immunoprecipitation (co-IP) confirmed that CEMIP interacted with TSP4 through the G8 domain. Further experiments confirmed that CEMIP promoted TSP4 degradation in lysosomes in an ACTN4-dependent manner, thereby activating the FAK signaling pathway.
Significance:
Our findings suggest that CEMIP significantly contributes to cardiac remodeling post-MI, which might be a novel approach for treating cardiac fibrosis following MI.
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