Document Detail

Electrophilic fatty acids regulate matrix metalloproteinase activity and expression.
MedLine Citation:
PMID:  21454668     Owner:  NLM     Status:  MEDLINE    
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.
Gustavo Bonacci; Francisco J Schopfer; Carlos I Batthyany; Tanja K Rudolph; Volker Rudolph; Nicholas K H Khoo; Eric E Kelley; Bruce A Freeman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-03-15
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-05-02     Completed Date:  2011-07-01     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  16074-81     Citation Subset:  IM    
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MeSH Terms
Carcinogens / pharmacology
Cell Line
Enzyme Activation / drug effects
Enzyme Precursors / biosynthesis*,  genetics
Gene Expression Regulation, Enzymologic*
Hypoglycemic Agents / pharmacology
Inflammation / enzymology,  genetics,  pathology
Matrix Metalloproteinase 9 / biosynthesis*,  genetics
Metalloendopeptidases / biosynthesis*,  genetics
Mice, Knockout
Oleic Acids / metabolism,  pharmacology*
PPAR gamma / antagonists & inhibitors,  genetics,  metabolism
Protein Structure, Tertiary
Tetradecanoylphorbol Acetate / pharmacology
Thiazolidinediones / pharmacology
Transcription, Genetic / drug effects,  genetics
Grant Support
Reg. No./Substance:
0/Carcinogens; 0/Enzyme Precursors; 0/Hypoglycemic Agents; 0/Oleic Acids; 0/PPAR gamma; 0/Thiazolidinediones; 122320-73-4/rosiglitazone; EC 3.4.24.-/Metalloendopeptidases; EC 3.4.24.-/pro-matrix metalloproteinase 9; EC 3.4.24.-/promatrilysin; EC Metalloproteinase 9; NI40JAQ945/Tetradecanoylphorbol Acetate

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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