Forestalling age-impaired angiogenesis and blood flow by targeting NOX : Interplay of NOX1, IL-6, and SASP in propagating cell senescence
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:118 |
|---|---|
| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 118(2021), 42 vom: 19. Okt. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Li, Yao [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Aging |
|---|
| Anmerkungen: |
Date Completed 20.12.2021 Date Revised 16.04.2022 published: Print figshare: 10.6084/m9.figshare.12724664 Citation Status MEDLINE |
|---|
| doi: |
10.1073/pnas.2015666118 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM331952009 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM331952009 | ||
| 003 | DE-627 | ||
| 005 | 20231225214614.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1073/pnas.2015666118 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1106.xml |
| 035 | |a (DE-627)NLM331952009 | ||
| 035 | |a (NLM)34654740 | ||
| 035 | |a (PII)e2015666118 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Li, Yao |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Forestalling age-impaired angiogenesis and blood flow by targeting NOX |b Interplay of NOX1, IL-6, and SASP in propagating cell senescence |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 20.12.2021 | ||
| 500 | |a Date Revised 16.04.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a figshare: 10.6084/m9.figshare.12724664 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a IL-6 | |
| 650 | 4 | |a NADPH oxidase | |
| 650 | 4 | |a aging | |
| 650 | 4 | |a endothelium | |
| 650 | 4 | |a senescence | |
| 650 | 7 | |a Interleukin-6 |2 NLM | |
| 650 | 7 | |a interleukin-6, mouse |2 NLM | |
| 650 | 7 | |a NADPH Oxidases |2 NLM | |
| 650 | 7 | |a EC 1.6.3.- |2 NLM | |
| 700 | 1 | |a Kračun, Damir |e verfasserin |4 aut | |
| 700 | 1 | |a Dustin, Christopher M |e verfasserin |4 aut | |
| 700 | 1 | |a El Massry, Mohamed |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Shuai |e verfasserin |4 aut | |
| 700 | 1 | |a Goossen, Christian J |e verfasserin |4 aut | |
| 700 | 1 | |a DeVallance, Evan R |e verfasserin |4 aut | |
| 700 | 1 | |a Sahoo, Sanghamitra |e verfasserin |4 aut | |
| 700 | 1 | |a St Hilaire, Cynthia |e verfasserin |4 aut | |
| 700 | 1 | |a Gurkar, Aditi U |e verfasserin |4 aut | |
| 700 | 1 | |a Finkel, Toren |e verfasserin |4 aut | |
| 700 | 1 | |a Straub, Adam C |e verfasserin |4 aut | |
| 700 | 1 | |a Cifuentes-Pagano, Eugenia |e verfasserin |4 aut | |
| 700 | 1 | |a Pagano, Patrick J |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Proceedings of the National Academy of Sciences of the United States of America |d 1915 |g 118(2021), 42 vom: 19. Okt. |w (DE-627)NLM000008982 |x 1091-6490 |7 nnns |
| 773 | 1 | 8 | |g volume:118 |g year:2021 |g number:42 |g day:19 |g month:10 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1073/pnas.2015666118 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 118 |j 2021 |e 42 |b 19 |c 10 | ||