PT  - JOURNAL ARTICLE
AU  - Ben J. Wu
AU  - Nick Di Girolamo
AU  - Konstanze Beck
AU  - Colm G. Hanratty
AU  - Katherine Choy
AU  - Jing Y. Hou
AU  - Michael R. Ward
AU  - Roland Stocker
TI  - Probucol [4,4′-[(1-Methylethylidene)bis(thio)]bis-[2,6-bis(1,1-dimethylethyl)phenol]] Inhibits Compensatory Remodeling and Promotes Lumen Loss Associated with Atherosclerosis in Apolipoprotein E-Deficient Mice
AID  - 10.1124/jpet.106.118612
DP  - 2007 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 477--484
VI  - 321
IP  - 2
4099  - http://jpet.aspetjournals.org/content/321/2/477.short
4100  - http://jpet.aspetjournals.org/content/321/2/477.full
SO  - J Pharmacol Exp Ther2007 May 01; 321
AB  - Probucol [4,4′-[(1-methylethylidene)bis(thio)]bis-[2,6-bis(1,1-dimethylethyl)phenol]] was withdrawn from the United States market because it failed to inhibit atherosclerosis in human femoral arteries, yet the drug was shown subsequently to inhibit atherosclerosis in human carotid arteries, and probucol monosuccinate ester is presently being tested in a phase III clinical trial as an antiatherosclerotic compound based on its anti-inflammatory properties. Inflammatory macrophages are implicated in arterial remodeling associated with atherosclerosis, and probucol inhibits experimental atherosclerosis in part by decreasing macrophages in lesions. However, the impact of probucol on remodeling is unknown, although such knowledge could help explain why the drug's benefit on human atherosclerosis is controversial. We therefore examined the effect of probucol on remodeling of the common carotid artery in apolipoprotein E-deficient mice. We observed that during de novo atherosclerosis, plaque growth was fully compensated by expansive remodeling, such that lumen area was unaffected. Early lesions were composed almost entirely of macrophages, and their contribution to lesion area progressively decreased thereafter. Probucol significantly decreased plaque area, expression of vascular cell adhesion molecule-1, and proliferation of intimal cells, resulting in delayed macrophage accumulation in the vessel. Probucol also decreased the production and activity of matrix metalloproteinases-2 and -9, independent of the plasmin protease system, and this was associated with an inhibition of expansive remodeling, resulting in lumen loss. These studies show that probucol attenuates compensatory remodeling associated with de novo atherosclerosis, probably via its anti-inflammatory properties. Our findings suggest that lumen volume is not a suitable surrogate to assess the antiatherosclerotic activity of probucol and related drugs. The American Society for Pharmacology and Experimental Therapeutics