Fisetin alleviates cellular senescence through PTEN mediated inhibition of PKC?-NOX1 pathway in vascular smooth muscle cells

Reactive oxygen species (ROS) are a key risk factor of cellular senescence and age-related diseases, and protein kinase C (PKC) has been shown to activate NADPH oxidases (NOXs), which generate ROS. Although PKC acti-vation induces oxidative stress, leading to the cellular dysfunction in various cell types, the correlation between PKC and senescence has not been reported in vascular smooth muscle cell (VSMC). Several studies have indicated cellular senescence is accompanied by phosphatase and tensin homolog (PTEN) loss and that an interaction exists between PTEN and PKC. Therefore, we aimed to determine whether PTEN and PKC are associated with VSMC senescence and to investigate the mechanism involved. We found hydrogen peroxide (H2O2) decreased PTEN expression and increased PKC delta phosphorylation. Moreover, H2O2 upregulated the NOX1 subunits, p22phox and p47phox, and induced VSMC senescence via p53-p21 signaling pathway. We identified PKC delta activation contributed to VSMC senescence through activation of NOX1 and ROS production. However, fisetin inhibited cellular senescence induced by the PTEN-PKC delta-NOX1-ROS signaling pathway, and this anti-aging effect was attributed to reduced ROS production caused by suppressing NOX1 activation. These results suggest that the PTEN-PCK delta signaling pathway is directly related to senescence via NOX1 activation and that the downregulation of PKC delta by flavonoids provides a potential means of treating age-associated diseases.

Automated summary

Reactive oxygen species (ROS) are a key risk factor of cellular senescence and age-related diseases, and protein kinase C (PKC) has been shown to activate NADPH oxidases (NOXs), which generate ROS. The correlation between PKC and senescence has not been reported in vascular smooth muscle cell (VSMC). Our study revealed that H2O2 decreased PTEN expression, increased PKC delta phosphorylation, upregulated NOX1 subunits, and induced VSMC senescence via p53-p21 signaling pathway. However, fisetin inhibited cellular senescence induced by the PTEN-PKC delta-NOX1-ROS signaling pathway, suggesting that downregulation of PKC delta by flavonoids provides a potential means of treating age-associated diseases.