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

Yingqing Chen,Yuying Cao,Liping Liu,Feng Jiang,Shuo Yuan,Qianqian Wang,Qinggao Zhang,Guangyao Kong,T Michael De Silva

doi:10.1155/2021/9926284

Yingqing Chen, Yuying Cao + Show 7 more

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https://doi.org/10.1155/2021/9926284

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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.

Highlights

Cellular senescence is a process of permanent cell cycle arrest in response to various physiological and environmental stresses, including radiation, multiple anticancer drugs, and oxidative stress [1]
Cells were pretreated with CO-releasing molecular-A1 (CORM-A1) in a dose-dependent manner (0, 20, 40, and 80 μM) for 6 h followed by the administration of bleomycin (25 μg/ml) for 96 h
We treated cells with inactive CORM-A1 that is incapable of releasing carbon monoxide (CO) and found that iCORM-A1 showed no interference in p21 and senescence-associated secretory phenotype (SASP) levels in the presence of bleomycin (Figures 1(b)–1(e))

Summary

Introduction

Cellular senescence is a process of permanent cell cycle arrest in response to various physiological and environmental stresses, including radiation (ionizing and UV), multiple anticancer drugs (bleomycin and etoposide), and oxidative stress [1]. The positive effects of senescent cells include tumor suppression, muscle regeneration, and skin wound healing in young organisms. The detrimental effects of senescent cells have been observed in the context of age-related conditions, including cancer, cardiovascular diseases, neurodegeneration, diabetes, sarcopenia, and declining immune function in the elderly [2,3,4]. Senescent cells display several other differences from proliferative cells. These differences include the increase of senescenceassociated β-galactosidase (SA-β-gal) activity, phosphorylated H2A histone family member X (γ-H2AX) foci, cyclindependent kinase inhibitors (CDKIs), such as p21CIP1 and p16INK4a, and senescence-associated secretory phenotype (SASP) which consists of growth hormones, proinflammatory cytokines, chemokines, angiogenic factors, and extracellular matrix remodeling proteases [5, 6]. Recent observations have supported that the increased secretion of serine protease inhibitor plasminogen activator inhibitor 1 (PAI-1), a component of SASP, can accelerate the aging in mice, and which is a marker and a critical mediator of cellular

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