Adventitial application of the NADPH oxidase inhibitor apocynin in vivo reduces neointima formation and endothelial dysfunction in rabbits.
OBJECTIVE
Reactive oxygen species including superoxide have been shown to promote atherogenesis. We previously showed that a major source of superoxide, the NADPH oxidase system, is upregulated in the intima and adventitia during remodelling induced by periarterial collars in rabbits. We have now examined the action of the NADPH oxidase inhibitor apocynin, given via the adventitia, on the neointima formation and endothelial function in this model.


METHODS
Perivascular collars were implanted around the common carotid arteries of male NZW rabbits for 14 days to induce intimal thickening. The periarterial space of one collar was filled with apocynin (1 mM) while the contralateral collar with the vehicle (0.1% DMSO).


RESULTS
After 14 days, local treatment with apocynin via the adventitia, reduced superoxide generation. In addition, apocynin significantly reduced neointima formation and proliferation of cells in both the neointima and adventitia. Moreover, NO-dependent vasorelaxation to acetylcholine, which is normally impaired in collared arteries, was improved, and apocynin suppressed the endothelial expression of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1.


CONCLUSIONS
NADPH oxidase is implicated in vascular remodelling and superoxide-stimulated cell proliferation in the neointima contributes to intimal hyperplasia in this collar model. Targeting NADPH oxidase via adventitial drug delivery not only reduces superoxide generation, but also normalises endothelial cell function. Targeting the primary source of NADPH oxidase-derived superoxide is an effective approach to prevent deleterious arterial remodelling, providing a rationale for designing more efficacious and selective inhibitors of vascular NADPH oxidase as potential therapeutics for human vascular disease.
Bernard O'Brien Institute of Microsurgery, University of Melbourne, 42 Fitzroy Street, Fitzroy, Victoria 3065, Australia.
Elsa C
EC
Chan
Srinivasa R
SR
Datla
Rodney
R
Dilley
Haruyo
H
Hickey
Grant R
GR
Drummond
Gregory J
GJ
Dusting
D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002339:Carotid Arteries; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015815:Cell Adhesion Molecules / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003238:Connective Tissue / Q000187:drug effects / Q000378:metabolism*; D003864:Depression, Chemical; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation; D066298:In Vitro Techniques; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000032:analysis / Q000378:metabolism; D011817:Rabbits; D013194:Staining and Labeling; D013481:Superoxides / Q000032:analysis / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*; D014664:Vasodilation / Q000187:drug effects
D000098:Acetophenones; D015815:Cell Adhesion Molecules; D013481:Superoxides; D009569:Nitric Oxide; C056165:acetovanillone; D019255:NADPH Oxidases