Gasotransmitter CO Attenuates Bleomycin-Induced Fibroblast Senescence via Induction of Stress Granule Formation

Abstract

Cellular senescence is recognized as a phenomenon wherein a proliferative cell undergoes a permanent growth arrest. The accumulation of senescent cells over time can become harmful and result in diseases and physiological decline. Plasminogen activator inhibitor (PAI-1) is considered as a critical marker and mediator of cellular senescence. The formation of stress granules (SGs) could prevent senescence through the sequestration of PAI-1, and we previously suggested that exogenous carbon monoxide (CO) could induce SG assembly via integrated stress response (ISR). Although CO is known to possess anti-inflammatory, antioxidative, and antiapoptotic properties, whether it exerts antisenescent effect is still not well defined. Here, to address whether CO-induced SGs could protect against cellular senescence, we first treated lung fibroblasts with bleomycin (BLM) to establish DNA damage-induced cellular senescence, and observed a significant increase of several hallmarks of senescence through SA-β-gal staining, immunofluorescence, qRT-PCR, and Western blot assay. However, pre- and posttreatment of CO could remarkably attenuate these senescent phenotypes. According to our immunofluorescence results, CO-induced SGs could inhibit BLM-induced cellular senescence via sequestration of PAI-1, while it was abolished after the cotreatment of ISR inhibitor (ISRIB) due to the inhibition of SG assembly. Overall, our results proposed a novel role of CO in suppressing bleomycin-induced lung fibroblast senescence through the assembly of SGs.