The DOI matches its Crossref record; 15 of the 15 references it cites were found in a registry or an index.
Hyperactive S6K1 Mediates Oxidative Stress and Endothelial Dysfunction in Aging: Inhibition by Resveratrol
Open accessAbstract
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.
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Cites
Resveratrol improves health and survival of mice on a high-calorie diet
Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., Prabhu, V. V., Allard, J. S., Lopez-Lluch, G., Lewis, K., et al. (2006) · Nature · doi:10.1038/nature05354 · Cited by 4,290
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., Nadon, N. L., Wilkinson, J. E., Frenkel, K., Carter, C. S., et al. (2009) · Nature · doi:10.1038/nature08221 · Cited by 3,766
mTOR controls mitochondrial oxidative function through a YY1–PGC-1α transcriptional complex
Cunningham, J. T., Rodgers, J. T., Arlow, D. H., Vazquez, F., Mootha, V. K., & Puigserver, P. (2007) · Nature · doi:10.1038/nature06322 · Cited by 1,488
Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span
Selman, C., Tullet, J. M. A., Wieser, D., Irvine, E., Lingard, S. J., Choudhury, A. I., Claret, M., Al-Qassab, H., Carmignac, D., Ramadani, F., et al. (2009) · Science · doi:10.1126/science.1177221 · Cited by 1,120 · cited 1×
“. Evidence for a role of S6K1 in regulation of mouse lifespan has been presented recently”
BackgroundInfluence of TOR kinase on lifespan in C. elegans
Vellai, T., Takacs-Vellai, K., Zhang, Y., Kovacs, A. L., Orosz, L., & Müller, F. (2003) · Nature · doi:10.1038/426620a · Cited by 1,057
SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1
Pacholec, M., Bleasdale, J. E., Chrunyk, B., Cunningham, D., Flynn, D., Garofalo, R. S., Griffith, D., Griffor, M., Loulakis, P., Pabst, B., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.088682 · Cited by 915
Bhaskar, P. T., & Hay, N. (2007) · Developmental Cell · doi:10.1016/j.devcel.2007.03.020 · Cited by 798
Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology
Li, J.-M., & Shah, A. M. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00124.2004 · Cited by 773
Resveratrol stimulates AMP kinase activity in neurons
Dasgupta, B., & Milbrandt, J. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0610068104 · Cited by 723
Chen, C., Liu, Y., Liu, R., Ikenoue, T., Guan, K.-L., Liu, Y., & Zheng, P. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20081297 · Cited by 682
Cited by
A Novel Paradigm for Heart Failure With Preserved Ejection Fraction
Paulus, W. J., & Tschöpe, C. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2013.02.092 · Cited by 3,564
Effects and Mechanisms of Resveratrol on Aging and Age‐Related Diseases
Zhou, D.-D., Luo, M., Huang, S.-Y., Saimaiti, A., Shang, A., Gan, R.-Y., & Li, H.-B. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/9932218 · Cited by 363
Shen, C., Jiang, J., Yang, L., Wang, D., & Zhu, W. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13631 · Cited by 344
Yang, Z., & Ming, X.-F. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00533 · Cited by 290
Vascular senescence in cardiovascular and metabolic diseases
Katsuumi, G., Shimizu, I., Yoshida, Y., & Minamino, T. (2018) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2018.00018 · Cited by 196
Metadata
- Authors
- Rajapakse, A. G., Yepuri, G., Carvas, J. M., Stein, S., Matter, C. M., Scerri, I., Ruffieux, J., Montani, J.-P., Ming, X.-F., & Yang, Z.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-04-22
- Volume
- 6
- Issue
- 4
- Pages
- e19237
- ISSN
- 1932-6203 (ISSN-L)
- OpenAlex
- W2029044425
- Cited by
- 161
- References
- 15
- FWCI
- 6.74
- Type
- journal article
- Language
- en
- Open access
- gold
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- The paper
- Rajapakse, A. G., Yepuri, G., Carvas, J. M., Stein, S., Matter, C. M., Scerri, I., Ruffieux, J., Montani, J.-P., Ming, X.-F., & Yang, Z. (2011). Hyperactive S6K1 Mediates Oxidative Stress and Endothelial Dysfunction in Aging: Inhibition by Resveratrol. PLoS ONE. https://doi.org/10.1371/journal.pone.0019237
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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