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ACTIVATION OF CYTOSOLIC PHOSPHOLIPASE A2[alpha] THROUGH NITRIC OXIDE‐INDUCED S‐NITROSYLATION: INVOLVEMENT OF INDUCIBLE NITRIC OXIDE SYNTHASE AND CYCLOOXYGENASE‐2
Author(s) -
Xu Lihong,
Han Chang,
Lim Kyu,
Wu Tong
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1120.3
Subject(s) - nitric oxide , nitric oxide synthase , s nitrosylation , phospholipase a2 , phospholipase a , cytosol , chemistry , arachidonic acid , eicosanoid , nitrosylation , cyclooxygenase , biochemistry , microbiology and biotechnology , biology , enzyme , organic chemistry , cysteine
Cytosolic phospholipase A 2 α (cPLA 2 α) is the rate‐limiting key enzyme that releases arachidonic acid (AA) for eicosanoid production. This study describes that cPLA 2 α protein is S‐nitrosylated and its activity is enhanced by nitric oxide (NO). Forced expression of inducible nitric oxide synthase (iNOS) in human epithelial cells induced cPLA 2 α S‐nitrosylation, enhanced its catalytic activity and increased the release of AA. The iNOS‐induced cPLA 2 α activation is blocked by the specific iNOS inhibitor, 1400W. Addition of the NO donor, GSNO, to isolated cell lysates induced S‐nitrosylation of cPLA 2 α, in vitro . Incubation of cultured cells with the iNOS substrate L‐Arginine and NO donor significantly increased cPLA 2 α activity and AA release. Furthermore, COX‐2 induction or expression markedly enhanced iNOS‐induced cPLA 2 α S‐nitrosylation and activation, leading to 9, 23, 20 fold increase of AA release and 100, 38, 88 fold of PGE 2 production in A549, SG231, and HEK293 cells, respectively, whereas COX‐2 alone leads to less than 2 fold change. These results indicate that COX‐2 has the ability to enhance iNOS‐induced cPLA 2 α S‐nitrosylation and that maximal PG synthesis is achieved by the synergistic interaction among iNOS, cPLA 2 α and COX‐2. These findings disclose a novel link among cPLA 2 α, iNOS and COX‐2 which form a multiprotein complex leading to cPLA 2 α S‐nitrosylation and activation.