Nox4 NADPH oxidase mediates oxidative stress and apoptosis caused by TNF-α in cerebral vascular endothelial cells
Open accessAbstract
Inflammatory brain disease may damage cerebral vascular endothelium leading to cerebral blood flow dysregulation. The proinflammatory cytokine TNF-α causes oxidative stress and apoptosis in cerebral microvascular endothelial cells (CMVEC) from newborn pigs. We investigated contribution of major cellular sources of reactive oxygen species to endothelial inflammatory response. Nitric oxide synthase and xanthine oxidase inhibitors ( N ω-nitro-l-arginine and allopurinol) had no effect, while mitochondrial electron transport inhibitors (CCCP, 2-thenoyltrifluoroacetone, and rotenone) attenuated TNF-α-induced superoxide (O 2•−) and apoptosis. NADPH oxidase inhibitors (diphenylene iodonium and apocynin) greatly reduced TNF-α-evoked O 2•− generation and apoptosis. TNF-α rapidly increased NADPH oxidase activity in CMVEC. Nox4, the cell-specific catalytic subunit of NADPH oxidase, is highly expressed in CMVEC, contributes to basal O 2•− production, and accounts for a burst of oxidative stress in response to TNF-α. Nox4 small interfering RNA, but not Nox2, knockdown prevented oxidative stress and apoptosis caused by TNF-α in CMVEC. Nox4 is colocalized with HO-2, the constitutive isoform of heme oxygenase (HO), which is critical for endothelial protection against TNF-α toxicity. The products of HO activity, bilirubin and carbon monoxide (CO, as a CO-releasing molecule, CORM-A1), inhibited Nox4-generated O 2•− and apoptosis caused by TNF-α stimulation. We conclude that Nox4 is the primary source of inflammation- and TNF-α-induced oxidative stress leading to apoptosis in brain endothelial cells. The ability of CO and bilirubin to combat TNF-α-induced oxidative stress by inhibiting Nox4 activity and/or by O 2•− scavenging, taken together with close intracellular compartmentalization of HO-2 and Nox4 in cerebral vascular endothelium, may contribute to HO-2 cytoprotection against inflammatory cerebrovascular disease.
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Other regulators of NOX4 include TNF-α, hypoxia, and PDGF.
“Other regulators include TNF-α (70, 681, 884, 1048), hypoxia (455), and PDGF (487).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [70]
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- Authors
- Basuroy, S., Bhattacharya, S., Leffler, C. W., & Parfenova, H.
- Affiliations
- University of Tennessee Health Science Center (US)
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2009-03
- Volume
- 296
- Issue
- 3
- Pages
- C422-C432
- ISSN
- 0363-6143 (ISSN-L)
- 1522-1563
- PMC
- PMC2660262
- OpenAlex
- W2084744910
- Cited by
- 254
- References
- 58
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 9 · 2023: 6 · 2022: 9 · 2021: 15 · 2020: 12 · 2019: 14 · 2018: 11 · 2017: 16 · 2016: 14 · 2015: 11 · 2014: 21 · 2013: 23 · 2012: 20
- FWCI
- 15.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Cell Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL034059, R01HL099655)
- National Institute of Neurological Disorders and Stroke (R01NS063936, R01NS046385)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- NOX4, NADPH oxidase, TNF-α, oxidative stress, apoptosis, brain microvascular endothelial cells, superoxide, heme oxygenase-2, bilirubin, carbon monoxide, CO-releasing molecules, inflammation, cerebrovascular disease, diphenyleneiodonium, apocynin
- MeSH terms
- Animals, Animals, Newborn, Bilirubin, Carbon Monoxide, Cells, Cultured, Cerebral Cortex, Enzyme Inhibitors, Fluorescent Antibody Technique, Heme Oxygenase (Decyclizing), Inflammation, Swine, Tumor Necrosis Factor-alpha, Free Radical Scavengers, Apoptosis, Reactive Oxygen Species, Oxidative Stress, NADPH Oxidases, Cytoprotection, RNA Interference, RNA, Small Interfering, Endothelial Cells, Microvessels
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