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The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1.

Meijles, DN; Sahoo, S; Al Ghouleh, I; Amaral, JH; Bienes-Martinez, R; Knupp, HE; Attaran, S; Sembrat, JC; Nouraie, SM; Rojas, MM; et al. Meijles, DN; Sahoo, S; Al Ghouleh, I; Amaral, JH; Bienes-Martinez, R; Knupp, HE; Attaran, S; Sembrat, JC; Nouraie, SM; Rojas, MM; Novelli, EM; Gladwin, MT; Isenberg, JS; Cifuentes-Pagano, E; Pagano, PJ (2017) The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1. Sci Signal, 10 (501). eaaj1784. ISSN 1937-9145 https://doi.org/10.1126/scisignal.aaj1784
SGUL Authors: Meijles, Daniel Nathan

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Abstract

Senescent cells withdraw from the cell cycle and do not proliferate. The prevalence of senescent compared to normally functioning parenchymal cells increases with age, impairing tissue and organ homeostasis. A contentious principle governing this process has been the redox theory of aging. We linked matricellular protein thrombospondin 1 (TSP1) and its receptor CD47 to the activation of NADPH oxidase 1 (Nox1), but not of the other closely related Nox isoforms, and associated oxidative stress, and to senescence in human cells and aged tissue. In human endothelial cells, TSP1 promoted senescence and attenuated cell cycle progression and proliferation. At the molecular level, TSP1 increased Nox1-dependent generation of reactive oxygen species (ROS), leading to the increased abundance of the transcription factor p53. p53 mediated a DNA damage response that led to senescence through Rb and p21cip, both of which inhibit cell cycle progression. Nox1 inhibition blocked the ability of TSP1 to increase p53 nuclear localization and p21cip abundance and its ability to promote senescence. Mice lacking TSP1 showed decreases in ROS production, p21cip expression, p53 activity, and aging-induced senescence. Conversely, lung tissue from aging humans displayed increases in the abundance of vascular TSP1, Nox1, p53, and p21cip Finally, genetic ablation or pharmacological blockade of Nox1 in human endothelial cells attenuated TSP1-mediated ROS generation, restored cell cycle progression, and protected against senescence. Together, our results provide insights into the functional interplay between TSP1 and Nox1 in the regulation of endothelial senescence and suggest potential targets for controlling the aging process at the molecular level.

Item Type: Article
Additional Information: This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Signaling on Vol. 10 17 Oct 2017, DOI: 10.1126/scisignal.aaj1784.
Keywords: Adult, Aged, Aging, Animals, CD47 Antigen, Cell Line, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p21, Endothelial Cells, Female, Gene Expression Regulation, Humans, Lung, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, NADPH Oxidase 1, RNA Interference, Reactive Oxygen Species, Signal Transduction, Thrombospondin 1, Tumor Suppressor Protein p53, Lung, Cell Line, Endothelial Cells, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Reactive Oxygen Species, Thrombospondin 1, Signal Transduction, Gene Expression Regulation, RNA Interference, Aging, Adult, Aged, Middle Aged, Female, Male, Tumor Suppressor Protein p53, Cyclin-Dependent Kinase Inhibitor p21, NADPH Oxidase 1, Cellular Senescence, CD47 Antigen, 0601 Biochemistry And Cell Biology
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Sci Signal
ISSN: 1937-9145
Language: eng
Dates:
DateEvent
17 October 2017Published
20 September 2017Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
R42 AA024003NIAAA NIH HHSUNSPECIFIED
T32 GM008424NIGMS NIH HHSUNSPECIFIED
P01 HL103455NHLBI NIH HHSUNSPECIFIED
R01 HL112914NHLBI NIH HHSUNSPECIFIED
K23 HL112848NHLBI NIH HHSUNSPECIFIED
R01 HL108954NHLBI NIH HHSUNSPECIFIED
R21 EB017184NIBIB NIH HHSUNSPECIFIED
R01 HL098032NHLBI NIH HHSUNSPECIFIED
R01 HL079207NHLBI NIH HHSUNSPECIFIED
R01 HL123766NHLBI NIH HHSUNSPECIFIED
R01 HL125886NHLBI NIH HHSUNSPECIFIED
T32 HL007563NHLBI NIH HHSUNSPECIFIED
T32 HL110849NHLBI NIH HHSUNSPECIFIED
PubMed ID: 29042481
Web of Science ID: WOS:000413108800001
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/109343
Publisher's version: https://doi.org/10.1126/scisignal.aaj1784

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