PMID- 22186670
OWN - NLM
STAT- MEDLINE
DCOM- 20120703
LR  - 20211021
IS  - 1559-7016 (Electronic)
IS  - 0271-678X (Print)
IS  - 0271-678X (Linking)
VI  - 32
IP  - 5
DP  - 2012 May
TI  - Nitrative stress in cerebral endothelium is mediated by mGluR5 in 
      hyperhomocysteinemia.
PG  - 825-34
LID - 10.1038/jcbfm.2011.185 [doi]
AB  - 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.
FAU - Mayo, Jamie N
AU  - Mayo JN
AD  - Department of Biological Sciences, Idaho State University, Pocatello, ID 83209, 
      USA.
FAU - Beard, Richard S Jr
AU  - Beard RS Jr
FAU - Price, Tulin O
AU  - Price TO
FAU - Chen, Cheng-Hung
AU  - Chen CH
FAU - Erickson, Michelle A
AU  - Erickson MA
FAU - Ercal, Nuran
AU  - Ercal N
FAU - Banks, William A
AU  - Banks WA
FAU - Bearden, Shawn E
AU  - Bearden SE
LA  - eng
GR  - P20 RR016454/RR/NCRR NIH HHS/United States
GR  - NIH P20 RR-016454/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20111221
PL  - United States
TA  - J Cereb Blood Flow Metab
JT  - Journal of cerebral blood flow and metabolism : official journal of the 
      International Society of Cerebral Blood Flow and Metabolism
JID - 8112566
RN  - 0 (2-chloro-5-hydroxyphenylglycine)
RN  - 0 (Amidines)
RN  - 0 (Benzylamines)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Excitatory Amino Acid Agonists)
RN  - 0 (Grm5 protein, mouse)
RN  - 0 (N-(3-(aminomethyl)benzyl)acetamidine)
RN  - 0 (Phenylacetates)
RN  - 0 (Receptor, Metabotropic Glutamate 5)
RN  - 0 (Receptors, Metabotropic Glutamate)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 3604-79-3 (3-nitrotyrosine)
RN  - 42HK56048U (Tyrosine)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 1.14.13.39 (Nos2 protein, mouse)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - Amidines/pharmacology
MH  - Animals
MH  - Benzylamines/pharmacology
MH  - Brain/blood supply/*metabolism
MH  - Endothelium/*metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Excitatory Amino Acid Agonists/pharmacology
MH  - Gene Expression Regulation, Enzymologic/drug effects/genetics
MH  - Glycine/analogs & derivatives/pharmacology
MH  - Homocysteine/genetics/metabolism
MH  - Hyperhomocysteinemia/genetics/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Nitric Oxide/genetics/*metabolism
MH  - Nitric Oxide Synthase Type II/antagonists & inhibitors/biosynthesis/genetics
MH  - Phenylacetates/pharmacology
MH  - Receptor, Metabotropic Glutamate 5
MH  - Receptors, Metabotropic Glutamate/agonists/antagonists & 
      inhibitors/genetics/*metabolism
MH  - *Stress, Physiological
MH  - Tyrosine/analogs & derivatives/genetics/metabolism
PMC - PMC3345916
EDAT- 2011/12/22 06:00
MHDA- 2012/07/04 06:00
PMCR- 2013/05/01
CRDT- 2011/12/22 06:00
PHST- 2011/12/22 06:00 [entrez]
PHST- 2011/12/22 06:00 [pubmed]
PHST- 2012/07/04 06:00 [medline]
PHST- 2013/05/01 00:00 [pmc-release]
AID - jcbfm2011185 [pii]
AID - 10.1038/jcbfm.2011.185 [doi]
PST - ppublish
SO  - J Cereb Blood Flow Metab. 2012 May;32(5):825-34. doi: 10.1038/jcbfm.2011.185. 
      Epub 2011 Dec 21.