CARD10 deficiency attenuates myocardial infarction associated with enhanced cardiac fibroblast senescence
TL;DR
It is suggested that CARD10 deficiency is associated with enhanced fibroblast senescence and improved post-MI remodeling, potentially involving mitochondrial dysfunction and PI3K/AKT signaling, highlighting CARD10 may represent a promising target for the treatment of MI.
Abstract
Aim: Myocardial infarction (MI) causes cardiomyocyte death and triggers tissue repair and remodeling processes orchestrated by multiple cell types, particularly cardiac fibroblasts (CFs). Caspase recruitment domain-containing protein 10 (CARD10) has been implicated in mitochondrial function and aneurysm formation; however, its role in MI is not clear. To investigate the potential role of CARD10 in MI and the underlying mechanisms. Methods: CARD10 expression and localization were analyzed by Western blot and immunofluorescence in mouse and human heart tissues. CARD10-deficient (Card10-/- ) and wild-type (WT) mice were subjected to experimental MI. Cardiac structure and function were assessed by echocardiography, histological analysis, and triphenyltetrazolium chloride (TTC). Cellular senescence was evaluated in vivo and in primary CFs using senescence-associated β-galactosidase (SA-β-gal) staining and the expression of p16 and phosphorylated histone H2A.X (gH2A.X). Mitochondrial dysfunction was assessed by JC-1 staining, mitochondrial reactive oxidative species (mtROS) measurements, and transmission electron microscopy. Potential signaling pathways were investigated by Western blot analysis. Results: Following MI, CARD10 expression was increased in the infarct border zone and was predominantly localized with CFs. Card10 -/- attenuated myocardial injury, improved cardiac remodeling, and enhanced fibroblast senescence. In vitro, transforming growth factor-beta (TGF-β)-stimulated Card10-/- CFs exhibited increased senescence, accompanied by elevated secretion of senescence-associated secretory phenotype (SASP) factors. Conditioned media from Card10-/- CFs promoted endothelial cell proliferation and angiogenesis. Furthermore, Card10-/- CFs exhibited severe mitochondrial dysfunction and activation of the phosphoinositide 3-kinase (PI3K) /protein kinase B (AKT) signaling pathway. Conclusion : These findings suggest that CARD10 deficiency is associated with enhanced fibroblast senescence and improved post-MI remodeling, potentially involving mitochondrial dysfunction and PI3K/AKT signaling, highlighting CARD10 may represent a promising target for the treatment of MI.