Nitrated oleic acid up-regulates PPARgamma and attenuates experimental inflammatory bowel disease.
Nitric oxide and its metabolites undergo nitration reactions with unsaturated fatty acids during oxidative inflammatory conditions, forming electrophilic nitro-fatty acid derivatives. These endogenous electrophilic mediators activate anti-inflammatory signaling reactions, serving as high-affinity ligands for peroxisome proliferator-activated receptor gamma (PPARgamma). Here we examined the therapeutic effects of 9- or 10-nitro-octadecenoic oleic acid (OA-NO(2)) and native oleic acid (OA) in a mouse model of colitis. OA-NO(2) reduced the disease activity index and completely prevented dextran sulfate sodium-induced colon shortening and the increase in colonic p65 expression. Increased PPARgamma expression was observed in colon samples as well as in cells after OA-NO(2) administration, whereas no effect was seen with OA. This induction of PPARgamma expression was completely abolished by the PPARgamma antagonist GW9662. 5-Aminosalicylic acid, an anti-inflammatory drug routinely used in the management of inflammatory bowel disease, also increased PPARgamma expression but to a lesser extent. Altogether, these findings demonstrate that administration of OA-NO(2) attenuates colonic inflammation and improves clinical symptoms in experimental inflammatory bowel disease. This protection involves activation of colonic PPARgamma.
Borniquel
Sara
S
Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.
Jansson
Emmelie A
EA
Cole
Marsha P
MP
Freeman
Bruce A
BA
Lundberg
Jon O
JO
D000818:Animals; D018929:Cell Culture Techniques / Q000379:methods; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005609:Free Radicals; D015971:Gene Expression Regulation, Enzymologic; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000378:metabolism*; D019804:Mesalamine / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism; D019301:Oleic Acid / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D015854:Up-Regulation
D005227:Fatty Acids; D005609:Free Radicals; D047495:PPAR gamma; D019301:Oleic Acid; D009569:Nitric Oxide; D019804:Mesalamine