Nitro-fatty acid inhibition of neointima formation after endoluminal vessel injury.
BACKGROUND
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.


RESULTS
The in vivo administration (21 days) of nitro-oleic acid (OA-NO(2)) inhibited neointimal hyperplasia after wire injury of the femoral artery in a murine model (OA-NO(2) 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-NO(2) 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-NO(2)-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-NO(2) in vivo, because inhibition of neointimal hyperplasia following femoral artery injury was abolished in HO-1(-/-) mice (OA-NO(2)-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.
Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pa., USA.
Marsha P
MP
Cole
Tanja K
TK
Rudolph
Nicholas K H
NK
Khoo
Uche N
UN
Motanya
Franca
F
Golin-Bisello
Jeffrey W
JW
Wertz
Francisco J
FJ
Schopfer
Volker
V
Rudolph
Steven R
SR
Woodcock
Subhashini
S
Bolisetty
Muhammad S
MS
Ali
Jifeng
J
Zhang
Y Eugene
YE
Chen
Anupam
A
Agarwal
Bruce A
BA
Freeman
Philip M
PM
Bauer
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D005263:Femoral Artery / Q000201:enzymology* / Q000293:injuries*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D009574:Nitro Compounds / Q000378:metabolism / Q000494:pharmacology*; D009829:Oleic Acids / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D017539:Tunica Intima / Q000201:enzymology*; D015854:Up-Regulation / Q000187:drug effects
D009574:Nitro Compounds; D009829:Oleic Acids; D010982:Platelet-Derived Growth Factor; D009569:Nitric Oxide; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat