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Genetic Evidence that Cerebrovascular Responses to Arachidonic Acid are Mediated by Hydrogen Peroxide Produced by SOD‐1
Author(s) -
Faraci Frank M.,
Modrick Mary L.,
Lynch Cynthia,
Dayal Sanjana,
Lentz Steven R.,
Didion Sean P.
Publication year - 2007
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.21.6.a1384-d
Subject(s) - glutathione peroxidase , arachidonic acid , chemistry , superoxide , reactive oxygen species , medicine , endocrinology , superoxide dismutase , in vivo , vasodilation , hydrogen peroxide , basilar artery , biochemistry , biology , oxidative stress , enzyme , microbiology and biotechnology
Arachidonic acid (AA) is a key molecule in vascular biology. Divergent mechanisms, including generation of reactive oxygen species and hydrogen peroxide (H2O2), have been proposed to mediate effects of AA on vascular tone. In this study, mice overexpressing glutathione peroxidase (GPx‐1), which degrades H2O2, were used to examine mechanisms by which AA affects blood vessels. Real‐time RT‐PCR indicated that vascular expression of GPx‐1 mRNA was increased 2.5‐fold in transgenic (Tg) mice compared to non‐transgenic (non‐Tg) littermates. In basilar arteries in vitro and in cerebral arterioles in vivo, AA produced dilation in non‐Tg mice and this response was markedly reduced in Tg mice (P<0.05). For example, 1 μM AA dilated the basilar artery by 53±5 and 7±2% in non‐Tg and GPx‐1 Tg mice, respectively. Responses to AA were also greatly reduced in mice deficient in superoxide dismutase (SOD‐1, which converts superoxide to H2O2) suggesting that SOD‐1 is the primary source of H2O2. In contrast, vasodilation to acetylcholine was not altered in GPx‐1 Tg mice suggesting that H2O2 plays no role in this response. Thus, overexpression of GPx‐1 almost completely prevents AA‐induced effects on cerebral vascular tone. These results provide the first evidence that GPx‐1 has functional effects in the cerebral circulation and that H2O2, produced by SOD‐1, is a key mediator of AA‐induced dilation in cerebral arteries and microvessels.