Department of Pharmacology, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
Smart-aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
PLoS One. 2020 Sep 30;15(9):e0239976. doi: 10.1371/journal.pone.0239976. eCollection 2020.
Cellular senescence is associated with inflammation and the senescence-associated secretory phenotype (SASP) of secreted proteins. Vascular smooth muscle cell (VSMC) expressing the SASP contributes to chronic vascular inflammation, loss of vascular function, and the developments of age-related diseases. Although VSMC senescence is well recognized, the mechanism of VSMC senescence and inflammation has not been established. In this study, we aimed to determine whether prednisolone (PD) attenuates adriamycin (ADR)-induced VSMC senescence and inflammation through the SIRT1-AMPK signaling pathway. We found that PD inhibited ADR-induced VSMC senescence and inflammation response by decreasing p-NF-κB expression through the SIRT1-AMPK signaling pathway. In addition, Western blotting revealed PD not only increased SIRT1 expression but also increased the phosphorylation of AMPK at Ser485 in ADR-treated VSMC. Furthermore, siRNA-mediated downregulation or pharmacological inhibitions of SIRT1 or AMPK significantly augmented ADR-induced inflammatory response and senescence in VSMC despite PD treatment. In contrast, the overexpression of SIRT1 or constitutively active AMPKα (CA-AMPKα) attenuated cellular senescence and p-NF-κB expression. Taken together, the inhibition of p-NF-κB by PD through the SIRT1 and p-AMPK (Ser485) pathway suppressed VSMC senescence and inflammation. Collectively, our results suggest that anti-aging effects of PD are caused by reduced VSMC senescence and inflammation due to reciprocal regulation of the SIRT1/p-AMPK (Ser485) signaling pathway.
细胞衰老与炎症和分泌蛋白的衰老相关分泌表型 (SASP) 有关。表达 SASP 的血管平滑肌细胞 (VSMC) 有助于慢性血管炎症、血管功能丧失和与年龄相关疾病的发展。尽管 VSMC 衰老已得到广泛认可，但 VSMC 衰老和炎症的机制尚未确定。在这项研究中，我们旨在确定泼尼松龙 (PD) 是否通过 SIRT1-AMPK 信号通路减弱阿霉素 (ADR) 诱导的 VSMC 衰老和炎症反应。我们发现 PD 通过 SIRT1-AMPK 信号通路降低 p-NF-κB 表达来抑制 ADR 诱导的 VSMC 衰老和炎症反应。此外，Western blot 显示 PD 不仅增加了 SIRT1 的表达，而且还增加了 ADR 处理的 VSMC 中 AMPK 的 Ser485 磷酸化。此外，尽管 PD 治疗，但 SIRT1 或 AMPK 的 siRNA 介导下调或药理学抑制显著增强了 ADR 诱导的 VSMC 炎症反应和衰老。相比之下，SIRT1 或组成型激活的 AMPKα (CA-AMPKα) 的过表达减轻了细胞衰老和 p-NF-κB 表达。总之，PD 通过 SIRT1 和 p-AMPK (Ser485) 通路抑制 p-NF-κB，从而抑制 VSMC 衰老和炎症。总之，我们的研究结果表明，PD 的抗衰老作用是由于 SIRT1/p-AMPK (Ser485) 信号通路的相互调节而导致 VSMC 衰老和炎症减少所致。
