The role of CCN5 in cellular senescence

Abstract

Cardiovascular diseases (CVDs) remain the leading cause of global mortality. Cellular senescence has recently been implicated in the pathogenesis of various cardiovascular diseases. Our group has previously shown that the matricellular protein CCN5 is a potent anti-fibrotic molecule capable of inhibiting and reversing cardiac fibrosis. In this study, we investigated whether CCN5 can modulate cellular senescence in the heart using diverse cellular types and multiple senescence induction methods (Replication, TGF-β, H2O2, and Doxorubicin). We utilized three established readouts: Western blotting for p53 and p21, staining for senescence-associated β-galactosidase (SA-β-gal), and microscopic analysis of γH2AX-positive foci. CCN5 effectively inhibited senescence in both cardiac myoblasts and fibroblasts. Furthermore, CCN5 suppressed secondary senescence in cardiac myoblasts induced by the Senescence-Associated Secretory Phenotype (SASP) factors secreted from cardiac fibroblasts, and vice versa. Critically, CCN5 also restored the apoptotic response of senescent cells. Mechanistically, we determined that CCN5 is internalized via clathrin-mediated endocytosis, translocates into the nucleus, and exerts its anti-senescence activity primarily through the p53-p21 pathway. Finally, CCN5 attenuated myocardial infarction (MI)-induced cellular senescence in mice in vivo. Collectively, our findings establish CCN5 as a novel anti-senescence regulator (senomorphic) and provide novel mechanistic insights into its action, suggesting a strong potential role in the development of anti-senescence therapies for heart diseases.