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Cited by 133Nitric Oxide and Endothelin EffectsTelomeres, Telomerase, and SenescenceMitochondrial Function and Pathology

The DOI matches its Crossref record; 146 of the 149 references it cites were found in a registry or an index.

NADPH Oxidases and Mitochondria in Vascular Senescence

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Salazar, Gloria·2018·International Journal of Molecular Sciences
DOI 10.3390/ijms19051327PMC PMC5983750
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Abstract

Aging is the major risk factor in the development of cardiovascular diseases (CVDs), including hypertension, atherosclerosis, and myocardial infarction. Oxidative stress caused by overproduction of reactive oxygen species (ROS) and/or by reduced expression of antioxidant enzymes is a major contributor to the progression of vascular senescence, pathologic remodeling of the vascular wall, and disease. Both oxidative stress and inflammation promote the development of senescence, a process by which cells stop proliferating and become dysfunctional. This review focuses on the role of the mitochondria and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases Nox1 and Nox4 in vascular senescence, and their contribution to the development of atherosclerosis. Recent findings are reviewed, supporting a critical role of the mitochondrial regulator peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1α (PGC-1α), the inflammatory gene nuclear factor κB (NF-κB), zinc, the zinc transporters (ZnTs) ZnT3 and ZnT10, and angiotensin II (Ang II) in mitochondrial function, and their role in telomere stability, which provides new mechanistic insights into a previously proposed unified theory of aging.

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Figure 1 Molecular pathways involved in senescence. Persistent DNA damage response (DDR) activates the ATM/p53/p21 pathway to stop the cell cycle, while preventing lysosomal acidification that inhibits autophagy, and activating NF-κB that induces senescence associated secretory phenotype (SASP). mTOR and reactive oxygen species (ROS) can induce senescence by DDR-independent mechanisms through the p38MAPK/NF-κB/SASP pathway. mTOR can also inhibit autophagy by a NF-κB-independent mechanism to induce senescence. Altogether, cell cycle arrest, reduced autophagy, and secretion of SASP components mediate vascular dysfunction and accelerated aging.
Figure 1 Molecular pathways involved in senescence. Persistent DNA damage response (DDR) activates the ATM/p53/p21 pathway to stop the cell cycle, while preventing lysosomal acidification that inhibits autophagy, and activating NF-κB that induces senescence associated secretory phenotype (SASP). mTOR and reactive oxygen species (ROS) can induce senescence by DDR-independent mechanisms through the p38MAPK/NF-κB/SASP pathway. mTOR can also inhibit autophagy by a NF-κB-independent mechanism to induce senescence. Altogether, cell cycle arrest, reduced autophagy, and secretion of SASP components mediate vascular dysfunction and accelerated aging.CC BY · PubMed Central
Figure 2 The role of Ang II in vascular senescence. Ang II binding to AT1R activates signal transduction pathways, including phosphorylation of p38MAPK, a driver of the SASP, and Akt, a negative regulator of PGC-1α function. Akt phosphorylates PGC-1α, increasing its acetylation, which reduces the binding of PGC-1α/FoxO1 (forkhead box O 1) to catalase and Sirt1(silence information regulator 2-like 1) promoters, reducing the expression of these target genes. Reduced Sirt1 expression further increases PGC-1α and FoxO1 acetylation, creating a negative feedback loop. Ang II also increases cytosolic zinc levels, leading to mitochondrial zinc accumulation that causes mitochondrial dysfunction and mitochondrial ROS (MitoROS) production that mediates NF-κB activation and Nox1 expression. NF-κB drives the SASP, and also mediates Nox4 upregulation and oxidative stress. Sirt1 inhibits senescence by deacetylating NF-κB, PGC-1α and FoxO1, thus improving mitochondrial function and the antioxidant capacity, while zinc induces senescence by causing mitochondrial dysfunction, increasing Nox1 and reducing catalase expression. SASP stimulates senescence in bystander cells.
Figure 2 The role of Ang II in vascular senescence. Ang II binding to AT1R activates signal transduction pathways, including phosphorylation of p38MAPK, a driver of the SASP, and Akt, a negative regulator of PGC-1α function. Akt phosphorylates PGC-1α, increasing its acetylation, which reduces the binding of PGC-1α/FoxO1 (forkhead box O 1) to catalase and Sirt1(silence information regulator 2-like 1) promoters, reducing the expression of these target genes. Reduced Sirt1 expression further increases PGC-1α and FoxO1 acetylation, creating a negative feedback loop. Ang II also increases cytosolic zinc levels, leading to mitochondrial zinc accumulation that causes mitochondrial dysfunction and mitochondrial ROS (MitoROS) production that mediates NF-κB activation and Nox1 expression. NF-κB drives the SASP, and also mediates Nox4 upregulation and oxidative stress. Sirt1 inhibits senescence by deacetylating NF-κB, PGC-1α and FoxO1, thus improving mitochondrial function and the antioxidant capacity, while zinc induces senescence by causing mitochondrial dysfunction, increasing Nox1 and reducing catalase expression. SASP stimulates senescence in bystander cells.CC BY · PubMed Central
Figure 3 PGC-1α and Nox1 in telomere and mitochondrial dysfunction during aging. Telomere dysfunction induces mitochondrial dysfunction through the p53-dependent downregulation of PGC-1α. Dysfunctional mitochondria produce mitochondrial ROS (MitoROS) that activates NF-κB-dependent upregulation of Nox1, causing telomere attrition and replicative senescence. Ang II induces senescence by inhibiting PGC-1α function, while zinc overload causes senescence by increasing MitoROS and Nox1 expression. In conditions of stress, Nox4 localizes in the mitochondria, also contributing to MitoROS production.
Figure 3 PGC-1α and Nox1 in telomere and mitochondrial dysfunction during aging. Telomere dysfunction induces mitochondrial dysfunction through the p53-dependent downregulation of PGC-1α. Dysfunctional mitochondria produce mitochondrial ROS (MitoROS) that activates NF-κB-dependent upregulation of Nox1, causing telomere attrition and replicative senescence. Ang II induces senescence by inhibiting PGC-1α function, while zinc overload causes senescence by increasing MitoROS and Nox1 expression. In conditions of stress, Nox4 localizes in the mitochondria, also contributing to MitoROS production.CC BY · PubMed Central
Figure 4 Proposed role of Nox1 and Nox4 in senescence. Hydrogen peroxide associated with basal Nox4 activity in physiological conditions protects from senescence, while overproduction of hydrogen peroxide during aging and stress conditions may promote senescence. Binding of zinc to the E-loop of Nox4 or oxidation of cysteine residues in the E-loop in response to stress conditions by overexpression of Nox1 could change the function of Nox4. Altered production of superoxide by Nox4 could mediate senescence in conditions of stress. Red arrows indicate increased expression.
Figure 4 Proposed role of Nox1 and Nox4 in senescence. Hydrogen peroxide associated with basal Nox4 activity in physiological conditions protects from senescence, while overproduction of hydrogen peroxide during aging and stress conditions may promote senescence. Binding of zinc to the E-loop of Nox4 or oxidation of cysteine residues in the E-loop in response to stress conditions by overexpression of Nox1 could change the function of Nox4. Altered production of superoxide by Nox4 could mediate senescence in conditions of stress. Red arrows indicate increased expression.CC BY · PubMed Central

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Metadata

Authors
Salazar, G.
Affiliations
Florida State University (US)
Corresponding author
Salazar, Gloria
ORCID
Salazar, Gloria
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2018-04-29
Volume
19
Issue
5
Pages
1327
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms19051327
PMC
PMC5983750
OpenAlex
W2800217088
Cited by
133
References
149
Citations by year
2026: 5 · 2025: 14 · 2024: 21 · 2023: 14 · 2022: 27 · 2021: 18 · 2020: 17 · 2019: 14 · 2018: 3
FWCI
1.71
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
American Heart Association (14GRNT20180028)
Topics
  • Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
vascular aging, NADPH oxidase, NOX1, NOX4, mitochondria, oxidative stress, reactive oxygen species, atherosclerosis, PGC-1α, NF-κB, zinc transporters, ZnT3, zinc, angiotensin II, telomere stability, aging, cardiovascular disease, inflammation
MeSH terms
Animals, Blood Vessels, Humans, Mitochondria, Cellular Senescence, Oxidative Stress, NADPH Oxidases, Atherosclerosis

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