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Homocysteine disrupts NO metabolism in brain microvascular endothelial cells by an mGluR5‐dependent mechanism
Author(s) -
Beard Richard Scott,
Henry Jamie N.,
Price Tulin Otamis,
Ercal Nuran,
Banks William A.,
Bearden Shawn E.
Publication year - 2011
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.25.1_supplement.820.11
Homocysteine (Hcy) impairs endothelial function by decreasing nitric oxide (NO) bioavailability and inducing endothelial cell (EC) nitrosative stress. We tested the hypothesis that Hcy disrupts NO metabolism of brain microvascular endothelium by activating metabotropic glutamate receptor 5 (mGluR5). Glutathione was lower and protein 3‐nitrotyrosinylation (3‐NT) was higher in brain microvessels isolated from a hyperhomocysteinemic mouse model ( cbs +/− ) compared with wild‐type littermates (p <0.05). Plasma NO x (nitrite + nitrate) was concomitantly decreased in cbs +/− vs. wild‐type littermates (p < 0.05). Using a brain microvascular endothelial cell line (bEnd.3), Hcy increased 3‐NT (Western blot and ELISA) in a dose (2–180μM) and time (1–9 days) dependent manner (p < 0.01), which was attenuated with MPEP (10–40μM at 48 hrs), an mGluR5 specific antagonist (p < 0.05). CHPG (25μM for 48 hrs), an mGluR5 specific agonist, increased bEnd.3 3‐NT expression (p < 0.01). Expression of inducible NO synthase significantly increased throughout 9‐days of treatment with Hcy (20μM; p < 0.05). NO x in the culture media was decreased by Hcy treatment in a dose (10–1000μM)‐dependent manner (p < 0.01). These data provide evidence that Hcy disrupts NO metabolism in brain microvascular endothelium by an mGluR5‐dependent mechanism. Supported by NIH #P20RR016454 and ISU FRC1019.