Fisetin alleviates cellular senescence through PTEN mediated inhibition of PKCδ-NOX1 pathway in vascular smooth muscle cells. (May 2023)

• Record Type: Journal Article
• Authors: Kim, Seul Gi; Sung, Jin Young; Kang, Young Jin; Choi, Hyoung Chul
• Is Part Of: Archives of gerontology and geriatrics. Volume 108(2023)
• Publication Date: 2023-05
• Subjects: PKCδ -- NADPH oxidase 1 -- Fisetin -- Senescence -- Vascular smooth muscle cell; AMPK AMP-activated protein kinase -- Ang II angiotensin II -- bpV bisperoxovanadium -- BSA bovine serum albumin -- DAPI 4′, 6-Diamidino-2-Phenylindole -- H2DCFDA 2′, 7′-dichlorodihydrofluorescein diacetate -- H2O2 hydrogen peroxide -- MAPK mitogen-activated protein kinases -- MnSOD manganese-dependent superoxide dismutase -- mTORC2 mTOR complex 2 -- NAC N-acetyl-L-cysteine -- PIC protease inhibitor cocktail I -- PKA protein kinase A -- PKC protein kinase C -- PTEN phosphatase and tensin homolog -- ROS reactive oxygen species -- SA-β-gal senescence-associated β-galactosidase -- SASP senescence-associated secretory phenotype -- TERT telomerase reverse transcriptase -- VSMC vascular smooth muscle cell; Aging -- Periodicals; Geriatrics -- Periodicals; Gerontology -- Periodicals; Electronic journals; 305.26
• DOI: 10.1016/j.archger.2023.104927
• Languages: English
• ISSNs: 0167-4943

Abstract

Highlights: VSMC senescence was accompanied by decreased PTEN and increased PKCδ phosphorylation. PKCδ activates NOX1, leading to ROS production and cellular senescence in VSMC. Fisetin is a polyphenol with antioxidant, anti-inflammatory, and anti-cancer effects. Fisetin alleviates senescence through PTEN mediated inhibition of PKCδ-NOX1 in VSMC. Abstract: 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 activation 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 (H2 O2 ) decreased PTEN expression and increased PKCδ phosphorylation. Moreover, H2 O2 upregulated the NOX1 subunits, p22 phox and p47 phox, and induced VSMC senescence via p53-p21 signaling pathway. We identified PKCδ activation contributed to VSMC senescence through activation of NOX1 and ROS production. However, fisetin inhibited cellular senescence induced by the PTEN-PKCδ-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-PCKδ signaling pathway is directly related to senescence via NOX1 activation and that the downregulation of PKCδ by flavonoids provides a potential means of treating age-associated diseases.