KIAA1199/CEMIP knockdown attenuates cardiac remodeling post myocardial infarction by activating TSP4 pathway in mice

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. 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. 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. Our findings suggest that CEMIP significantly contributes to cardiac remodeling post-MI, which might be a novel approach for treating cardiac fibrosis following MI. [Display omitted] •CEMIP knockdown attenuates cardiac remodeling post myocardial infarction by activating TSP4 pathway in mice.•CEMIP interacted with TSP4 by the G8 domain, inducing degradation of TSP4 protein through the lysosomal pathway in an ACTN4-dependent fashion.•The ameliorative impact of CEMIP knockdown on adverse cardiac remodeling was nullified upon TSP4 knockdown.