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.
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Submitted on : Tuesday, April 3, 2012 - 8:48:48 PM
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Gustavo Bonacci, Francisco J Schopfer, Carlos I Batthyany, Tanja K Rudolph, Volker Rudolph, et al.. Electrophilic fatty acids regulate matrix metalloproteinase activity and expression.. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2011, 286 (18), pp.16074-81. ⟨10.1074/jbc.M111.225029⟩. ⟨pasteur-00685059⟩

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