title: Hyperactive S6K1 mediates oxidative stress and endothelial dysfunction in aging: inhibition by resveratrol.
abstract: Mammalian target of rapamycin (mTOR)/S6K1 signalling emerges as a critical regulator of aging. Yet, a role of mTOR/S6K1 in aging-associated vascular endothelial dysfunction remains unknown. In this study, we investigated the role of S6K1 in aging-associated endothelial dysfunction and effects of the polyphenol resveratrol on S6K1 in aging endothelial cells. We show here that senescent endothelial cells displayed higher S6K1 activity, increased superoxide production and decreased bioactive nitric oxide (NO) levels than young endothelial cells, which is contributed by eNOS uncoupling. Silencing S6K1 in senescent cells reduced superoxide generation and enhanced NO production. Conversely, over-expression of a constitutively active S6K1 mutant in young endothelial cells mimicked endothelial dysfunction of the senescent cells through eNOS uncoupling and induced premature cellular senescence. Like the mTOR/S6K1 inhibitor rapamycin, resveratrol inhibited S6K1 signalling, resulting in decreased superoxide generation and enhanced NO levels in the senescent cells. Consistent with the data from cultured cells, an enhanced S6K1 activity, increased superoxide generation, and decreased bioactive NO levels associated with eNOS uncoupling were also detected in aortas of old WKY rats (aged 20-24 months) as compared to the young animals (1-3 months). Treatment of aortas of old rats with resveratrol or rapamycin inhibited S6K1 activity, oxidative stress, and improved endothelial NO production. Our data demonstrate a causal role of the hyperactive S6K1 in eNOS uncoupling leading to endothelial dysfunction and vascular aging. Resveratrol improves endothelial function in aging, at least in part, through inhibition of S6K1. Targeting S6K1 may thus represent a novel therapeutic approach for aging-associated vascular disease.
authors.affiliation: Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland.
authors.forename: Angana G
authors.initials: AG
authors.lastname: Rajapakse
authors.forename: Gautham
authors.initials: G
authors.lastname: Yepuri
authors.forename: João M
authors.initials: JM
authors.lastname: Carvas
authors.forename: Sokrates
authors.initials: S
authors.lastname: Stein
authors.forename: Christian M
authors.initials: CM
authors.lastname: Matter
authors.forename: Isabelle
authors.initials: I
authors.lastname: Scerri
authors.forename: Jean
authors.initials: J
authors.lastname: Ruffieux
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Montani
authors.forename: Xiu-Fen
authors.initials: XF
authors.lastname: Ming
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D011921:Rats, Inbred WKY; D000077185:Resveratrol; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D013267:Stilbenes; D013481:Superoxides; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; C526901:Rps6kb1 protein, rat; D000077185:Resveratrol