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Cited by 285Pulmonary Hypertension Research and TreatmentsNitric Oxide and Endothelin EffectsRedox biology and oxidative stress

Hypoxia activates NADPH oxidase to increase [ROS]i and [Ca2+]i through the mitochondrial ROS-PKCɛ signaling axis in pulmonary artery smooth muscle cells

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Rathore, Rakesh, Zheng, Yun-Min, Niu, Chun-Feng, Liu, Qing-Hua, Korde, Amit, Ho, Ye-Shih, Wang, Yong-Xiao·2008·Free Radical Biology and Medicine
DOI 10.1016/j.freeradbiomed.2008.06.012PMC PMC2586914
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Abstract

The importance of NADPH oxidase (Nox) in hypoxic responses in hypoxia-sensing cells, including pulmonary artery smooth muscle cells (PASMCs), remains uncertain. In this study, using Western blot analysis we found that the major Nox subunits Nox1, Nox4, p22(phox), p47(phox), and p67(phox) were equivalently expressed in mouse pulmonary and systemic (mesenteric) arteries. However, acute hypoxia significantly increased Nox activity and translocation of p47(phox) protein to the plasma membrane in pulmonary, but not mesenteric, arteries. The Nox inhibitor apocynin and p47(phox) gene deletion attenuated the hypoxic increase in intracellular concentrations of reactive oxygen species and Ca(2+) ([ROS](i) and [Ca(2+)](i)), as well as contractions in mouse PASMCs, and abolished the hypoxic activation of Nox in pulmonary arteries. The conventional/novel protein kinase C (PKC) inhibitor chelerythrine, specific PKCepsilon translocation peptide inhibitor, and PKCepsilon gene deletion, but not the conventional PKC inhibitor GO6976, prevented the hypoxic increase in Nox activity in pulmonary arteries and [ROS](i) in PASMCs. The PKC activator phorbol 12-myristate 13-acetate could increase Nox activity in pulmonary and mesenteric arteries. Inhibition of mitochondrial ROS generation with rotenone or myxothiazol prevented hypoxic activation of Nox. Glutathione peroxidase-1 (Gpx1) gene overexpression to enhance H(2)O(2) removal significantly inhibited the hypoxic activation of Nox, whereas Gpx1 gene deletion had the opposite effect. Exogenous H(2)O(2) increased Nox activity in pulmonary and mesenteric arteries. These findings suggest that acute hypoxia may distinctively activate Nox to increase [ROS](i) through the mitochondrial ROS-PKCepsilon signaling axis, providing a positive feedback mechanism to contribute to the hypoxic increase in [ROS](i) and [Ca(2+)](i) as well as contraction in PASMCs.

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Crossref · 10.1016/j.freeradbiomed.2008.06.012

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  • In a murine myocardial infarction model, nitrite decreases infarct size, and this effect is lost in Mb KO mice, which cannot reduce nitrite to NO.

    “In a murine myocardial infarction (MI) model, nitrite has been shown to decrease infarct size, and this effect was lost in Mb KO mice, which cannot reduce nitrite to NO (774).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [774]

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Authors
Rathore, R., Zheng, Y.-M., Niu, C.-F., Liu, Q.-H., Korde, A., Ho, Y.-S., & Wang, Y.-X.
Affiliations
  • Albany Medical College (US)
  • Wayne State University (US)
Corresponding author
Wang, Yong-Xiao
ORCID
Korde, Amit
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2008-11
Volume
45
Issue
9
Pages
1223-1231
ISSN
0891-5849 (ISSN-L)
DOI
10.1016/j.freeradbiomed.2008.06.012
PMC
PMC2586914
OpenAlex
W2030576423
Cited by
283
References
58
Citations by year
2026: 4 · 2025: 13 · 2024: 1 · 2023: 9 · 2022: 17 · 2021: 13 · 2020: 9 · 2019: 18 · 2018: 15 · 2017: 21 · 2016: 18 · 2015: 15 · 2014: 20 · 2013: 27 · 2012: 22
FWCI
18.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Free Radical Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5p30es006639-15)
  • National Heart, Lung, and Blood Institute (R01HL064043, R01HL075190)
  • National Institute of Environmental Health Sciences (P-30-ES06639, P30-ES006639)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
hypoxia, NADPH oxidase, pulmonary artery smooth muscle cells, reactive oxygen species, intracellular calcium, protein kinase C epsilon, mitochondrial reactive oxygen species, p47phox translocation, glutathione peroxidase 1, hydrogen peroxide, vasoconstriction, apocynin, p22phox, p67phox
MeSH terms
Animals, Hypoxia, Calcium, Enzyme Inhibitors, Mice, Transgenic, Mitochondria, Models, Biological, Pulmonary Artery, Signal Transduction, Gene Expression Regulation, Enzymologic, Reactive Oxygen Species, NADPH Oxidases, Myocytes, Smooth Muscle, Mice, Protein Kinase C-epsilon

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