Copyright © 2007, European Society of Cardiology
Adventitial application of the NADPH oxidase inhibitor apocynin in vivo reduces neointima formation and endothelial dysfunction in rabbits
aBernard O'Brien Institute of Microsurgery, University of Melbourne, 42 Fitzroy Street, Fitzroy, Victoria 3065, Australia
bDepartments of Surgery and Pharmacology, University of Melbourne, Victoria 3010, Australia
cHoward Florey Institute, University of Melbourne, Victoria 3010, Australia
dDepartment of Pharmacology, Monash University, Victoria 3800, Australia
eCentre for Vascular Health, Monash University, Victoria 3800, Australia
* Corresponding author. Bernard O'Brien Institute of Microsurgery, University of Melbourne, 42 Fitzroy Street, Fitzroy, Victoria 3065, Australia. Tel.: +61 3 9288 4047; fax: +61 3 9416 0926. dusting{at}unimelb.edu.au
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.
KEYWORDS Adventitial drug delivery; Apocynin; Cell proliferation; Endothelial dysfunction; NADH oxidase; Neointima formation; Perivascular collar-induced remodelling