Nitro-Fatty Acid Inhibition of Neointima Formation After Endoluminal Vessel Injury

• Published in: Circulation research Vol. 105; no. 10; pp. 965 - 972
• Main Authors: Cole, Marsha P, Rudolph, Tanja K, Khoo, Nicholas K.H, Motanya, Uche N, Golin-Bisello, Franca, Wertz, Jeffrey W, Schopfer, Francisco J, Rudolph, Volker, Woodcock, Steven R, Bolisetty, Subhashini, Ali, Muhammad S, Zhang, Jifeng, Chen, Y Eugene, Agarwal, Anupam, Freeman, Bruce A, Bauer, Philip M
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 06.11.2009; Lippincott Williams & Wilkins
• Subjects: Animals; Biological and medical sciences; Cell Movement - drug effects; Femoral Artery - enzymology; Femoral Artery - injuries; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic - drug effects; Heme Oxygenase (Decyclizing) - biosynthesis; Inflammation - metabolism; Mice; Mice, Knockout; Nitric Oxide - metabolism; Nitro Compounds - metabolism; Nitro Compounds - pharmacology; Oleic Acids - metabolism; Oleic Acids - pharmacology; Oxidation-Reduction - drug effects; Platelet-Derived Growth Factor - pharmacology; Rats; Tunica Intima - enzymology; Up-Regulation - drug effects; Vertebrates: cardiovascular system; Stenosis; arteries; Lipids; Fatty acids; Artery; Vertebrata; Mammalia; Blood vessel; Nitric oxide; Circulatory system; Inhibition; Lesion; Formation
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.109.199075

RATIONALE:Fatty acid nitroalkenes are endogenously generated electrophilic byproducts of nitric oxide and nitrite-dependent oxidative inflammatory reactions. Existing evidence indicates nitroalkenes support posttranslational protein modifications and transcriptional activation that promote the resolution of inflammation. OBJECTIVE:The aim of this study was to assess whether in vivo administration of a synthetic nitroalkene could elicit antiinflammatory actions in vivo using a murine model of vascular injury. METHODS AND RESULTS:The in vivo administration (21 days) of nitro-oleic acid (OA-NO2) inhibited neointimal hyperplasia after wire injury of the femoral artery in a murine model (OA-NO2 treatment resulted in reduced intimal area and intima to media ratio versus vehicle- or oleic acid (OA)-treated animals, P<0.0001). Increased heme oxygenase (HO)-1 expression accounted for much of the vascular protection induced by OA-NO2 in both cultured aortic smooth muscle cells and in vivo. Inhibition of HO by Sn(IV)-protoporphyrin or HO-1 small interfering RNA reversed OA-NO2–induced inhibition of platelet-derived growth factor-stimulated rat aortic smooth muscle cell migration. The upregulation of HO-1 expression also accounted for the antistenotic actions of OA-NO2 in vivo, because inhibition of neointimal hyperplasia following femoral artery injury was abolished in HO-1 mice (OA-NO2–treated wild-type versus HO-1 mice, P=0.016). CONCLUSIONS:In summary, electrophilic nitro-fatty acids induce salutary gene expression and cell functional responses that are manifested by a clinically significant outcome, inhibition of neointimal hyperplasia induced by arterial injury.