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- Title
Nitrative stress in cerebral endothelium is mediated by mGluR5 in hyperhomocysteinemia.
- Authors
Mayo, Jamie N; Beard, Richard S; Price, Tulin O; Chen, Cheng-Hung; Erickson, Michelle A; Ercal, Nuran; Banks, William A; Bearden, Shawn E
- Abstract
Hyperhomocysteinemia (HHcy) disrupts nitric oxide (NO) signaling and increases nitrative stress in cerebral microvascular endothelial cells (CMVECs). This is mediated, in part, by protein nitrotyrosinylation (3-nitrotyrosine; 3-NT) though the mechanisms by which extracellular homocysteine (Hcy) generates intracellular 3-NT are unknown. Using a murine model of mild HHcy (cbs+/− mouse), we show that 3-NT is significantly elevated in cerebral microvessels with concomitant reductions in serum NO bioavailability as compared with wild-type littermate controls (cbs+/+). Directed pharmacology identified a receptor-dependent mechanism for 3-NT formation in CMVECs. Homocysteine increased expression of inducible NO synthase (iNOS) and formation of 3-NT, both of which were blocked by inhibition of metabotropic glutamate receptor-5 (mGluR5) with the specific antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride. Activation of mGluR5 is both sufficient and necessary to drive the nitrative stress because direct activation using the mGluR5-specific agonist (RS)-2-chloro-5-hydroxyphenylglycine also increased iNOS expression and 3-NT formation while knockdown of mGluR5 receptor expression by short hairpin RNA (shRNA) blocked their increase in response to Hcy. Nitric oxide derived from iNOS was required for Hcy-mediated formation of 3-NT because the effect was blocked by 1400W. These results provide the first evidence for a receptor-dependent process that explains how plasma Hcy levels control intracellular nitrative stress in cerebral microvascular endothelium.
- Subjects
HYPERHOMOCYSTEINEMIA; VASCULAR endothelium; BRAIN blood-vessels; NITRIC-oxide synthases; CELLULAR signal transduction; BIOAVAILABILITY; GLUTAMATE receptors; GENE expression
- Publication
Journal of Cerebral Blood Flow & Metabolism, 2012, Vol 32, Issue 5, p825
- ISSN
0271-678X
- Publication type
Article
- DOI
10.1038/jcbfm.2011.185