PMID- 18181170
OWN - NLM
STAT- MEDLINE
DCOM- 20080429
LR  - 20211203
IS  - 1097-4652 (Electronic)
IS  - 0021-9541 (Print)
IS  - 0021-9541 (Linking)
VI  - 215
IP  - 3
DP  - 2008 Jun
TI  - Cytochrome P450 (CYP) 2J2 gene transfection attenuates MMP-9 via inhibition of 
      NF-kappabeta in hyperhomocysteinemia.
PG  - 771-81
LID - 10.1002/jcp.21356 [doi]
AB  - Hyperhomocysteinemia (HHcy) is associated with atherosclerotic events involving 
      the modulation of arachidonic acid (AA) metabolism and the activation of matrix 
      metalloproteinase-9 (MMP-9). Cytochrome P450 (CYP) epoxygenase-2J2 (CYP2J2) is 
      abundant in the heart endothelium, and its AA metabolites epoxyeicosatrienoic 
      acids (EETs) mitigates inflammation through NF-kappabeta. However, the underlying 
      molecular mechanisms for MMP-9 regulation by CYP2J2 in HHcy remain obscure. We 
      sought to determine the molecular mechanisms by which P450 epoxygenase gene 
      transfection or EETs supplementation attenuate homocysteine (Hcy)-induced MMP-9 
      activation. CYP2J2 was over-expressed in mouse aortic endothelial cells (MAECs) 
      by transfection with the pcDNA3.1/CYP2J2 vector. The effects of P450 epoxygenase 
      transfection or exogenous supplementation of EETs on NF-kappabeta-mediated MMP-9 
      regulation were evaluated using Western blot, in-gel gelatin zymography, 
      electromobility shift assay, immunocytochemistry. The result suggested that Hcy 
      downregulated CYP2J2 protein expression and dephosphorylated PI3K-dependent AKT 
      signal. Hcy induced the nuclear translocation of NF-kappabeta via downregulation 
      of IKbetaalpha (endogenous cytoplasmic inhibitor of NF-kappabeta). Hcy induced 
      MMP-9 activation by increasing NF-kappabeta-DNA binding. Moreover, P450 
      epoxygenase transfection or exogenous addition of 8,9-EET phosphorylated the AKT 
      and attenuated Hcy-induced MMP-9 activation. This occurred, in part, by the 
      inhibition of NF-kappabeta nuclear translocation, NF-kappabeta-DNA binding and 
      activation of IKbetaalpha. The study unequivocally suggested the pivotal role of 
      EETs in the modulation of Hcy/MMP-9 signal.
CI  - (c) 2008 Wiley-Liss, Inc.
FAU - Moshal, Karni S
AU  - Moshal KS
AD  - Department of Physiology and Biophysics, School of Medicine University of 
      Louisville, Louisville, Kentucky 40202, USA.
FAU - Zeldin, Darryl C
AU  - Zeldin DC
FAU - Sithu, Srinivas D
AU  - Sithu SD
FAU - Sen, Utpal
AU  - Sen U
FAU - Tyagi, Neetu
AU  - Tyagi N
FAU - Kumar, Munish
AU  - Kumar M
FAU - Hughes, William M Jr
AU  - Hughes WM Jr
FAU - Metreveli, Naira
AU  - Metreveli N
FAU - Rosenberger, Dorothea S E
AU  - Rosenberger DS
FAU - Singh, Mahavir
AU  - Singh M
FAU - Vacek, Thomas P
AU  - Vacek TP
FAU - Rodriguez, Walter E
AU  - Rodriguez WE
FAU - Ayotunde, Adeagbo
AU  - Ayotunde A
FAU - Tyagi, Suresh C
AU  - Tyagi SC
LA  - eng
GR  - HL-71010/HL/NHLBI NIH HHS/United States
GR  - Z01 ES025034-13/Intramural NIH HHS/United States
GR  - R01 HL071010/HL/NHLBI NIH HHS/United States
GR  - HL-88012/HL/NHLBI NIH HHS/United States
GR  - HL-74185 S/HL/NHLBI NIH HHS/United States
GR  - R01 HL074185/HL/NHLBI NIH HHS/United States
GR  - HL-74185/HL/NHLBI NIH HHS/United States
GR  - R01 HL088012/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cell Physiol
JT  - Journal of cellular physiology
JID - 0050222
RN  - 0 (I-kappa B Proteins)
RN  - 0 (Nfkbia protein, mouse)
RN  - 0 (Transcription Factor RelA)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - 81246-85-7 (8,9-epoxyeicosatrienoic acid)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.13.- (Oxygenases)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2J2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - FC398RK06S (8,11,14-Eicosatrienoic Acid)
SB  - IM
MH  - 8,11,14-Eicosatrienoic Acid/analogs & derivatives/pharmacology
MH  - Animals
MH  - Cells, Cultured
MH  - Cytochrome P-450 CYP2J2
MH  - Cytochrome P-450 Enzyme System/*genetics/*metabolism
MH  - Enzyme Activation/drug effects
MH  - Enzyme Induction/drug effects
MH  - Homocysteine/pharmacology
MH  - Hyperhomocysteinemia/enzymology/*metabolism
MH  - I-kappa B Proteins/metabolism
MH  - Matrix Metalloproteinase 9/biosynthesis/*metabolism
MH  - Mice
MH  - NF-KappaB Inhibitor alpha
MH  - Oxygenases/*genetics/*metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation/drug effects
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Transcription Factor RelA/*antagonists & inhibitors/metabolism
MH  - Transfection
PMC - PMC2364732
MID - NIHMS44472
EDAT- 2008/01/09 09:00
MHDA- 2008/04/30 09:00
PMCR- 2008/06/01
CRDT- 2008/01/09 09:00
PHST- 2008/01/09 09:00 [pubmed]
PHST- 2008/04/30 09:00 [medline]
PHST- 2008/01/09 09:00 [entrez]
PHST- 2008/06/01 00:00 [pmc-release]
AID - 10.1002/jcp.21356 [doi]
PST - ppublish
SO  - J Cell Physiol. 2008 Jun;215(3):771-81. doi: 10.1002/jcp.21356.