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Nox4 NADPH oxidase mediates oxidative stress and apoptosis caused by TNF‐alpha in cerebral vascular endothelial cells.
Author(s) -
Basuroy Shyamali,
Bhattacharya Sujoy,
Leffler Charles W,
Parfenova Helena
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.613.2
Subject(s) - nox4 , nadph oxidase , oxidative stress , apocynin , apoptosis , chemistry , endothelium , endothelial dysfunction , microbiology and biotechnology , biology , endocrinology , biochemistry
Inflammatory brain disease may damage cerebral vascular endothelium leading to cerebral blood flow dysregulation. The pro‐inflammatory cytokine TNFα causes oxidative stress and apoptosis in cerebral microvascular endothelial cells (CMVEC) from newborn pigs. We investigated contribution of NADPH oxidase (Nox family), a cellular source of superoxide (O 2· − ) to the endothelial inflammatory response. NADPH oxidase inhibitors (DPI and apocynin) greatly reduced TNFα‐evoked O 2· − generation and apoptosis. Among the Nox family members, Nox2 and Nox4 are expressed in CMVEC. Nox4 siRNA knockdown completely blocked oxidative stress and apoptosis caused by TNFα, while Nox2 siRNA knockdown only partially (by 20‐30%) attenuated apoptosis. Nox4 is co‐localized with HO‐2, the constitutive isoform of heme oxygenase (HO), which is critical for endothelial protection against TNFα toxicity. The product of HO activity, carbon monoxide (CO), inhibited TNFα induced Nox4 activity and apoptosis. We conclude that Nox4 is the primary source of inflammation‐ and TNFα‐induced oxidative stress leading to apoptosis in brain endothelial cells. The ability of CO to inhibit Nox4 activity, taken together with close intracellular compartmentalization of Nox4 and HO‐2 in cerebral vascular endothelium, may contribute to HO‐2 cytoprotection against inflammatory cerebrovascular disease.