Electrophilic fatty acids regulate matrix metalloproteinase activity and expression
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Electrophilic fatty acids regulate matrix metalloproteinase activity and expression. / Bonacci, Gustavo; Schopfer, Francisco J; Batthyany, Carlos I; Rudolph, Tanja K; Rudolph, Volker; Khoo, Nicholas K H; Kelley, Eric E; Freeman, Bruce A.
in: J BIOL CHEM, Jahrgang 286, Nr. 18, 06.05.2011, S. 16074-16081.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Electrophilic fatty acids regulate matrix metalloproteinase activity and expression
AU - Bonacci, Gustavo
AU - Schopfer, Francisco J
AU - Batthyany, Carlos I
AU - Rudolph, Tanja K
AU - Rudolph, Volker
AU - Khoo, Nicholas K H
AU - Kelley, Eric E
AU - Freeman, Bruce A
PY - 2011/5/6
Y1 - 2011/5/6
N2 - 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.
AB - 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.
KW - Animals
KW - Carcinogens/pharmacology
KW - Cell Line
KW - Enzyme Activation/drug effects
KW - Enzyme Precursors/biosynthesis
KW - Gene Expression Regulation, Enzymologic
KW - Humans
KW - Hypoglycemic Agents/pharmacology
KW - Inflammation/enzymology
KW - Matrix Metalloproteinase 9/biosynthesis
KW - Metalloendopeptidases/biosynthesis
KW - Mice
KW - Mice, Knockout
KW - Oleic Acids/metabolism
KW - PPAR gamma/antagonists & inhibitors
KW - Protein Structure, Tertiary
KW - Rosiglitazone
KW - Tetradecanoylphorbol Acetate/pharmacology
KW - Thiazolidinediones/pharmacology
KW - Transcription, Genetic/drug effects
U2 - 10.1074/jbc.M111.225029
DO - 10.1074/jbc.M111.225029
M3 - SCORING: Journal article
C2 - 21454668
VL - 286
SP - 16074
EP - 16081
JO - J BIOL CHEM
JF - J BIOL CHEM
SN - 0021-9258
IS - 18
ER -