Journal article

Hyperactive S6K1 mediates oxidative stress and endothelial dysfunction in aging: inhibition by resveratrol

  • Rajapakse, Angana Gupta Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland
  • Yepuri, Gautham Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland
  • Carvas, João M. Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland
  • Stein, Sokrates Cardiovascular Research, Institute of Physiology, University of Zurich and Cardiology, University Hospital Zurich, Zurich, Switzerland
  • Matter, Christian M. Cardiovascular Research, Institute of Physiology, University of Zurich and Cardiology, University Hospital Zurich, Zurich, Switzerland
  • Scerri, Isabelle Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland
  • Ruffieux, Jean Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland
  • Montani, Jean-Pierre Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland
  • Ming, Xiu-Fen Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland
  • Yang, Zhihong Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland
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    22.04.2011
Published in:
  • PLoS ONE. - 2011, vol. 6, no. 4, p. e19237
English 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.
Faculty
Faculté des sciences et de médecine
Department
Département de Médecine
Language
  • English
Classification
Biology
License
License undefined
Identifiers
Persistent URL
https://folia.unifr.ch/unifr/documents/301898
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