期刊
JOURNAL OF CELLULAR PHYSIOLOGY
卷 215, 期 3, 页码 771-781出版社
WILEY
DOI: 10.1002/jcp.21356
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资金
- Intramural NIH HHS [Z01 ES025034-13] Funding Source: Medline
- NHLBI NIH HHS [HL-88012, HL-74185 S, R01 HL074185, HL-74185, R01 HL071010, HL-71010, R01 HL088012] Funding Source: Medline
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-kappa beta. 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 epoxygerase 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-kappa beta-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-kappa beta via downregulation of IK beta alpha (endogenous cytoplasmic inhibitor of NF-kappa beta). Hcy induced MMP-9 activation by increasing NF-kappa beta-DNA binding. Moreover, P450 epoxygerase 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-kappa beta nuclear translocation, NF-kappa beta-DNA binding and activation of IK beta alpha. The study unequivocally suggested the pivotal role of EETs in the modulation of Hcy/MMP-9 signal.
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