title: Electrophilic fatty acids regulate matrix metalloproteinase activity and expression.
abstract: Nitro-fatty acids (NO(2)-FA) are electrophilic signaling mediators formed by reactions of nitric oxide and nitrite. NO(2)-FA exert anti-inflammatory signaling actions through post-translational protein modifications. We report that nitro-oleic acid (OA-NO(2)) stimulates proMMP-7 and proMMP-9 proteolytic activity via adduction of the conserved cysteine switch domain thiolate. Biotin-labeled OA-NO(2) showed this adduction occurs preferentially with latent forms of MMP, confirming a role for thiol alkylation by OA-NO(2) in MMP activation. In addition to regulating pro-MMP activation, MMP expression was modulated by OA-NO(2) via activation of peroxisome proliferator-activated receptor-γ. MMP-9 transcription was decreased in phorbol 12-myristate 13-acetate-stimulated THP-1 macrophages to an extent similar to that induced by the peroxisome proliferator-activated receptor-γ agonist Rosiglitazone. This was affirmed using a murine model of atherosclerosis, ApoE(-/-) mice, where in vivo OA-NO(2) administration suppressed MMP expression in atherosclerotic lesions. These findings reveal that electrophilic fatty acid derivatives can serve as effectors during inflammation, first by activating pro-MMP proteolytic activity via alkylation of the cysteine switch domain, and then by transcriptionally inhibiting MMP expression, thereby limiting the further progression of inflammatory processes.
authors: Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
authors: Gustavo
authors: G
authors: Bonacci
authors: Francisco J
authors: FJ
authors: Schopfer
authors: Carlos I
authors: CI
authors: Batthyany
authors: Tanja K
authors: TK
authors: Rudolph
authors: Volker
authors: V
authors: Rudolph
authors: Nicholas K H
authors: NK
authors: Khoo
authors: Eric E
authors: EE
authors: Kelley
authors: Bruce A
authors: BA
authors: Freeman
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009829:Oleic Acids / Q000378:metabolism / Q000494:pharmacology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D000077154:Rosiglitazone; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: D002273:Carcinogens; D004792:Enzyme Precursors; D007004:Hypoglycemic Agents; D009829:Oleic Acids; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D008666:Metalloendopeptidases; C120487:pro-matrix metalloproteinase 9; C099583:promatrilysin; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate