PMID- 18080868
OWN - NLM
STAT- MEDLINE
DCOM- 20080215
LR  - 20211020
IS  - 1062-3329 (Print)
IS  - 1029-2373 (Electronic)
IS  - 1026-793X (Linking)
VI  - 14
IP  - 6
DP  - 2007 Nov-Dec
TI  - gamma-Aminbuturic acid A receptor mitigates homocysteine-induced endothelial cell 
      permeability.
PG  - 315-23
AB  - Many cerebrovascular disorders are accompanied by an increased homocysteine (Hcy) 
      levels. We have previously shown that acute hyperhomocysteinemia (HHcy) leads to 
      an increased microvascular permeability in the mouse brain. Hcy competitively 
      binds to gamma -aminbuturic acid (GABA) receptors and may increase vascular 
      permeability by acting as an excitatory neurotransmitter. However, the role of 
      GABA-A (GABA(A)) receptor in Hcy-induced endothelial cell (EC) permeability 
      remains unclear. In the present study we attempted to determine the role of 
      GABA(A) receptor and the possible mechanisms involved in Hcy-induced EC layer 
      permeability. Mouse aortic and brain ECs were grown in Transwells and treated 
      with 50 mu M Hcy in the presence or absence of GABA(A)-specific agonist muscimol. 
      Role of matrix metalloproteinase-9 (MMP-9) was determined using its activity 
      inhibitor GM-6001. Involvement of extracellular signal-regulated kinase (ERK) 
      signaling was assessed using its kinase activity inhibitors PD98059 or U0126. EC 
      permeability to the known content of bovine serum albumin (BSA)-conjugated with 
      Alexa Flour-488 was assessed by measuring fluorescence intensity of the solutes 
      in the Transwell's lower chambers. It was found that Hcy induced the formation of 
      filamentous actin (F-actin). Hcy-induced EC permeability to BSA was significantly 
      decreased by GABA and muscimol treatments. Presence of MMP-9 or ERK kinase 
      activity inhibitors restored the Hcy-induced EC permeability to its baseline 
      level. The mediation BSA leakage through the ECs was further confirmed in the 
      experiments where Hcy-induced alterations in transendothelial electrical 
      resistance of confluent ECs were assessed. The data suggest that Hcy increases EC 
      layer permeability through inhibition of GABA(A) receptor and F-actin formation, 
      in part, by transducing ERK and MMP-9 activation.
FAU - Tyagi, Neetu
AU  - Tyagi N
AD  - Department of Physiology and Biophysics, University of Louisville, Louisville, 
      Kentucky 40292, USA.
FAU - Moshal, Karni S
AU  - Moshal KS
FAU - Tyagi, Suresh C
AU  - Tyagi SC
FAU - Lominadze, David
AU  - Lominadze D
LA  - eng
GR  - R01 HL071010/HL/NHLBI NIH HHS/United States
GR  - R01 HL080394/HL/NHLBI NIH HHS/United States
GR  - R01 HL080394-02/HL/NHLBI NIH HHS/United States
GR  - R01 NS051568/NS/NINDS NIH HHS/United States
PT  - Journal Article
PL  - England
TA  - Endothelium
JT  - Endothelium : journal of endothelial cell research
JID - 9412590
RN  - 0 (Actins)
RN  - 0 (Albumins)
RN  - 0 (Butadienes)
RN  - 0 (Dipeptides)
RN  - 0 (Flavonoids)
RN  - 0 (N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan 
      methylamide)
RN  - 0 (Nitriles)
RN  - 0 (Receptors, GABA-A)
RN  - 0 (U 0126)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 2763-96-4 (Muscimol)
RN  - 56-12-2 (gamma-Aminobutyric Acid)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
SB  - IM
MH  - Actins/metabolism
MH  - Albumins/metabolism
MH  - Animals
MH  - Aorta/cytology/drug effects/enzymology
MH  - Brain/cytology/drug effects
MH  - Butadienes/pharmacology
MH  - Capillary Permeability/*drug effects
MH  - Cell Membrane Permeability/*drug effects
MH  - Cells, Cultured
MH  - Dipeptides/pharmacology
MH  - Endothelial Cells/*cytology/*drug effects/enzymology
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Flavonoids/pharmacology
MH  - Homocysteine/*pharmacology
MH  - Mice
MH  - Muscimol/pharmacology
MH  - Nitriles/pharmacology
MH  - Phosphorylation/drug effects
MH  - Receptors, GABA-A/*metabolism
MH  - Vascular Resistance/drug effects
MH  - gamma-Aminobutyric Acid/pharmacology
PMC - PMC2819032
MID - NIHMS169040
EDAT- 2007/12/18 09:00
MHDA- 2008/02/19 09:00
PMCR- 2010/02/10
CRDT- 2007/12/18 09:00
PHST- 2007/12/18 09:00 [pubmed]
PHST- 2008/02/19 09:00 [medline]
PHST- 2007/12/18 09:00 [entrez]
PHST- 2010/02/10 00:00 [pmc-release]
AID - 788541613 [pii]
AID - 10.1080/10623320701746164 [doi]
PST - ppublish
SO  - Endothelium. 2007 Nov-Dec;14(6):315-23. doi: 10.1080/10623320701746164.