Published Online
on April 7, 2003

A more recent version of this article appeared on April 22, 2003

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Submitted on September 16, 2002
Revised on January 7, 2003
Accepted on January 14, 2003

Probucol Promotes Functional Reendothelialization in Balloon-Injured Rabbit Aortas

Antony K. Lau MBBS, FRACP, Steven B. Leichtweis PhD, Peter Hume BSc, Ryuichi Mashima PhD, Jing Y. Hou BSc, Xavier Chaufour MD, PhD, Barbara Wilkinson MSc, Nicholas H. Hunt PhD, David S. Celermajer MBBS, FRACP, PhD, and Roland Stocker PhD^*

From The Heart Research Institute (A.K.L., S.B.L., P.H., R.M., J.Y.H., D.S.C., R.S.), Departments of Vascular Surgery (X.C.), Pathology (N.H.H.), and Medicine (D.S.C.), University of Sydney, Skin and Cancer Foundation (B.W.), and University of New South Wales (R.S.), Sydney, Australia.

^* To whom correspondence should be addressed. E-mail: r.stocker{at}unsw.edu.au.

Background--Probucol remains the only conventional drug that reduces restenosis after coronary angioplasty. Apart from its weak cholesterol-lowering effect, probucol has antioxidant properties, but it remains unclear how this drug inhibits restenosis.

Methods and Results--Aortic balloon-injured New Zealand White rabbits were fed 2% (wt/wt) cholesterol-enriched or normal chow, with 0.75% (wt/wt) probucol (P) or without (controls, C) for 6 weeks. Endothelial denudation of the abdominal aorta was performed at week 3 with a 3F Fogarty embolectomy catheter. The arteries were harvested after week 6 and analyzed for histology, lipids and antioxidants, and endothelial regeneration and function. Probucol significantly decreased aortic intima-to-media ratio (cholesterol-fed: C, 1.10±0.08 versus P, 0.70±0.10; normal: C, 0.89±0.02 versus P, 0.83±0.05; P<0.05) and the numbers of proliferating intimal smooth muscle cells and lowered serum cholesterol without altering the proportion of aortic lipids that was oxidized. Probucol promoted endothelial regeneration in the injured aorta in cholesterol-fed rabbits (25% increase in reendothelialization, P<0.05) and in those on normal chow (37% increase, P<0.01). This was associated with both improved endothelial function as assessed by enhanced aortic ring relaxation and cGMP production in response to acetylcholine and decreased intimal thickening.

Conclusions--Probucol inhibits intimal thickening in balloon-damaged arteries of rabbits by promoting the regeneration of functional endothelium, without affecting the proportion of aortic lipids that was oxidized. This novel in vivo finding helps explain how probucol inhibits restenosis after coronary angioplasty and highlights potential new targets for therapeutic intervention.

Key words: angioplasty • antioxidants • atherosclerosis • endothelium • restenosis

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