PMID- 19308943
OWN - NLM
STAT- MEDLINE
DCOM- 20090514
LR  - 20231213
IS  - 1097-4652 (Electronic)
IS  - 0021-9541 (Print)
IS  - 0021-9541 (Linking)
VI  - 220
IP  - 1
DP  - 2009 Jul
TI  - Activation of GABA-A receptor ameliorates homocysteine-induced MMP-9 activation 
      by ERK pathway.
PG  - 257-66
LID - 10.1002/jcp.21757 [doi]
AB  - Hyperhomocysteinemia (HHcy) is a risk factor for neuroinflammatory and 
      neurodegenerative diseases. Homocysteine (Hcy) induces redox stress, in part, by 
      activating matrix metalloproteinase-9 (MMP-9), which degrades the matrix and 
      leads to blood-brain barrier dysfunction. Hcy competitively binds to 
      gamma-aminbutyric acid (GABA) receptors, which are excitatory neurotransmitter 
      receptors. However, the role of GABA-A receptor in Hcy-induced cerebrovascular 
      remodeling is not clear. We hypothesized that Hcy causes cerebrovascular 
      remodeling by increasing redox stress and MMP-9 activity via the extracellular 
      signal-regulated kinase (ERK) signaling pathway and by inhibition of GABA-A 
      receptors, thus behaving as an inhibitory neurotransmitter. Hcy-induced reactive 
      oxygen species production was detected using the fluorescent probe, 
      2'-7'-dichlorodihydrofluorescein diacetate. Hcy increased nicotinamide adenine 
      dinucleotide phosphate-oxidase-4 concomitantly suppressing thioredoxin. Hcy 
      caused activation of MMP-9, measured by gelatin zymography. The GABA-A receptor 
      agonist, muscimol ameliorated the Hcy-mediated MMP-9 activation. In parallel, Hcy 
      caused phosphorylation of ERK and selectively decreased levels of tissue 
      inhibitors of metalloproteinase-4 (TIMP-4). Treatment of the endothelial cell 
      with muscimol restored the levels of TIMP-4 to the levels in control group. Hcy 
      induced expression of iNOS and decreased eNOS expression, which lead to a 
      decreased NO bioavailability. Furthermore muscimol attenuated Hcy-induced MMP-9 
      via ERK signaling pathway. These results suggest that Hcy competes with GABA-A 
      receptors, inducing the oxidative stress transduction pathway and leading to ERK 
      activation.
FAU - Tyagi, Neetu
AU  - Tyagi N
AD  - Department of Physiology and Biophysics, School of Medicine, University of 
      Louisville, Louisville, Kentucky 40292, USA.
FAU - Gillespie, William
AU  - Gillespie W
FAU - Vacek, Jonathan C
AU  - Vacek JC
FAU - Sen, Utpal
AU  - Sen U
FAU - Tyagi, Suresh C
AU  - Tyagi SC
FAU - Lominadze, David
AU  - Lominadze D
LA  - eng
GR  - HL-80394/HL/NHLBI NIH HHS/United States
GR  - R01 HL080394-03/HL/NHLBI NIH HHS/United States
GR  - R01 HL080394/HL/NHLBI NIH HHS/United States
GR  - R01 HL071010/HL/NHLBI NIH HHS/United States
GR  - R01 NS051568/NS/NINDS NIH HHS/United States
GR  - R01 HL080394-04/HL/NHLBI NIH HHS/United States
GR  - NS-51568/NS/NINDS NIH HHS/United States
GR  - R01 HL071010-07/HL/NHLBI NIH HHS/United States
GR  - HL-71010/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - J Cell Physiol
JT  - Journal of cellular physiology
JID - 0050222
RN  - 0 (Collagen Type IV)
RN  - 0 (GABA Agonists)
RN  - 0 (GABA-A Receptor Agonists)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, GABA-A)
RN  - 0 (Tissue Inhibitor of Metalloproteinases)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 2763-96-4 (Muscimol)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 52500-60-4 (Thioredoxins)
RN  - 9007-58-3 (Elastin)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 1.14.13.39 (Nos2 protein, mouse)
RN  - EC 1.14.13.39 (Nos3 protein, mouse)
RN  - EC 1.6.3.- (NADPH Oxidase 4)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 1.6.3.- (Nox4 protein, mouse)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - EC 3.4.24.35 (Mmp9 protein, mouse)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Collagen Type IV/metabolism
MH  - Elastin/metabolism
MH  - Endothelial Cells/*drug effects/enzymology
MH  - Enzyme Activation
MH  - Extracellular Signal-Regulated MAP Kinases/*metabolism
MH  - GABA Agonists/*pharmacology
MH  - *GABA-A Receptor Agonists
MH  - Homocysteine/*metabolism
MH  - Matrix Metalloproteinase 9/*metabolism
MH  - Mice
MH  - Muscimol/*pharmacology
MH  - NADPH Oxidase 4
MH  - NADPH Oxidases/metabolism
MH  - Nitric Oxide/metabolism
MH  - Nitric Oxide Synthase Type II/metabolism
MH  - Nitric Oxide Synthase Type III/metabolism
MH  - Oxidative Stress/drug effects
MH  - Phosphorylation
MH  - Reactive Oxygen Species/metabolism
MH  - Receptors, GABA-A/metabolism
MH  - Signal Transduction/drug effects
MH  - Thioredoxins/metabolism
MH  - Tissue Inhibitor of Metalloproteinases/metabolism
MH  - Tissue Inhibitor of Metalloproteinase-4
PMC - PMC2811271
MID - NIHMS166868
EDAT- 2009/03/25 09:00
MHDA- 2009/05/15 09:00
PMCR- 2010/01/26
CRDT- 2009/03/25 09:00
PHST- 2009/03/25 09:00 [entrez]
PHST- 2009/03/25 09:00 [pubmed]
PHST- 2009/05/15 09:00 [medline]
PHST- 2010/01/26 00:00 [pmc-release]
AID - 10.1002/jcp.21757 [doi]
PST - ppublish
SO  - J Cell Physiol. 2009 Jul;220(1):257-66. doi: 10.1002/jcp.21757.