Published online before print September 24, 2009, doi: 10.1161/CIRCRESAHA.109.199075
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Submitted on April 13, 2009
Revised on September 11, 2009
Accepted on September 16, 2009
Nitro-Fatty Acid Inhibition of Neointima Formation After Endoluminal Vessel Injury
Marsha P. Cole ;
From the Departments of Pharmacology & Chemical Biology (M.P.C., T.K.R., N.K.H.K., U.N.M., F.G.-B., F.J.S., V.R., S.R.W., M.S.A., B.A.F., P.M.B.) and Surgery (J.W.W., P.M.B.), University of Pittsburgh, Pa; Cardiovascular Center (J.Z., Y.E.C.), Department of Internal Medicine, University of Michigan, Ann Arbor; and Department of Medicine (S.B., A.A.), Nephrology Research and Training Center, Department of Biochemistry and Molecular Genetics, University of Alabama, Birmingham.
* To whom correspondence should be addressed. E-mail: freerad{at}pitt.edu or bauerpm{at}upmc.edu.
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.
Key words: fatty acids • arteries • stenosis • nitric oxide