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TRPA1 mediates NADPH oxidase‐dependent cerebral artery dilation (1079.1)
Author(s) -
Sullivan Michelle,
Gonzales Albert,
Bruhl Allison,
Leo M.,
Jaggar Jonathan,
Welsh Donald,
Earley Scott
Publication year - 2014
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.28.1_supplement.1079.1
Subject(s) - chemistry , nadph oxidase , transient receptor potential channel , vasodilation , endogeny , nitric oxide , superoxide , biochemistry , reactive oxygen species , biophysics , pharmacology , medicine , receptor , enzyme , biology , organic chemistry
Activation of the Ca 2+ ‐permeable transient receptor potential (TRP) ankyrin (A) channel TRPA1 in the cerebral artery endothelium with electrophilic compounds induces dilation. Endogenous agonists for endothelial TRPA1 have not been reported. We hypothesized that H 2 O 2 is an endogenous agonist for TRPA1 in this tissue. H 2 O 2 can be generated by NADPH oxidase (NOX) activity via production of a O 2 ‐ intermediate or directly by NOX isoform NOX4. We find that activation of NOX with its substrate, NADPH, increases TRPA1 activity and induces dilation of pressurized cerebral arteries (80 mmHg) that is blocked by TRPA1 inhibitor HC‐030031 (HC) and H 2 O 2 degradation by catalase. In the presence of iron, H 2 O 2 is converted to highly reactive oxygen radicals, such as OH•, by the Fenton reaction. To distinguish between direct effects of H 2 O 2 vs. those of OH• or OH• metabolites we inhibited the Fenton reaction by chelating iron with deferoxamine. Deferoxamine attenuated NADPH‐induced TRPA1 activation and vasodilation, suggesting that OH• formation is required for NOX‐dependent TRPA1 activation. OH• peroxidizes membrane lipids yielding lipid peroxidation products (LPP). The LPP 4‐hydroxynonenal increased TRPA1 activity and induced cerebral artery dilation that was blocked by HC. Together, these data suggest that NOX‐dependent LPP generation activates TRPA1 in cerebral artery endothelial cells to induce vasodilation. Grant Funding Source : Supported by HL091905