气候变化领域集成服务门户(CCPortal): Forestalling age-impaired angiogenesis and blood flow by targeting NOX: Interplay of NOX1, IL-6, and SASP in propagating cell senescence

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DOI	10.1073/pnas.2015666118
	Forestalling age-impaired angiogenesis and blood flow by targeting NOX: Interplay of NOX1, IL-6, and SASP in propagating cell senescence
	Li Y.; Kračun D.; Dustin C.M.; El Massry M.; Yuan S.; Goossen C.J.; DeVallance E.R.; Sahoo S.; Hilaire C.St.; Gurkar A.U.; Finkel T.; Straub A.C.; Cifuentes-Pagano E.; Pagano P.J.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:42
英文摘要	In an aging population, intense interest has shifted toward prolonging health span. Mounting evidence suggests that cellular reactive species are propagators of cell damage, inflammation, and cellular senescence. Thus, such species have emerged as putative provocateurs and targets for senolysis, and a clearer understanding of their molecular origin and regulation is of paramount importance. In an inquiry into signaling triggered by aging and proxy instigator, hyperglycemia, we show that NADPH Oxidase (NOX) drives cell DNA damage and alters nuclear envelope integrity, inflammation, tissue dysfunction, and cellular senescence in mice and humans with similar causality. Most notably, selective NOX1 inhibition rescues age-impaired blood flow and angiogenesis, vasodilation, and the endothelial cell wound response. Indeed, NOX1i delivery in vivo completely reversed age-impaired hind-limb blood flow and angiogenesis while disrupting a NOX1-IL-6 senescence-associated secretory phenotype (SASP) proinflammatory signaling loop. Relevant to its comorbidity with age, clinical samples from diabetic versus nondiabetic subjects reveal as operant this NOX1-mediated vascular senescence and inflammation in humans. On a mechanistic level, our findings support a previously unidentified role for IL-6 in this feedforward inflammatory loop and peroxisome proliferator-activated receptor gamma (PPARγ) down-regulation as inversely modulating p65-mediated NOX1 transcription. Targeting this previously unidentified NOX1-SASP signaling axis in aging is predicted to be an effective strategy for mitigating senescence in the vasculature and other organ systems. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Aging; Endothelium; IL-6; NADPH oxidase; Senescence
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/238773
作者单位	Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, United States; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, United States; Center for Microvascular Research, University of Pittsburgh, Pittsburgh, PA 15261, United States; Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, United States; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, United States; Aging Institute of University of Pittsburgh Medical Center, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15219, United States; Division of Geriatric Medicine, Department of Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, United States; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, United States
推荐引用方式 GB/T 7714	Li Y.,Kračun D.,Dustin C.M.,et al. Forestalling age-impaired angiogenesis and blood flow by targeting NOX: Interplay of NOX1, IL-6, and SASP in propagating cell senescence[J],2021,118(42).
APA	Li Y..,Kračun D..,Dustin C.M..,El Massry M..,Yuan S..,...&Pagano P.J..(2021).Forestalling age-impaired angiogenesis and blood flow by targeting NOX: Interplay of NOX1, IL-6, and SASP in propagating cell senescence.Proceedings of the National Academy of Sciences of the United States of America,118(42).
MLA	Li Y.,et al."Forestalling age-impaired angiogenesis and blood flow by targeting NOX: Interplay of NOX1, IL-6, and SASP in propagating cell senescence".Proceedings of the National Academy of Sciences of the United States of America 118.42(2021).