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.
Probucol [4,4'-[(1-methylethylidene)bis(thio)]bis-[2,6-bis(1,1-dimethylethyl)phenol]] was withdrawn from the United States market because it failed to inhibit atherosclerosis in human femoral arteries, yet the drug was shown subsequently to inhibit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.
Wu
Ben J
BJ
Centre for Vascular Research and Inflammatory Diseases Research Unit, School of Medical Sciences, University of New South Wales, and Royal North Shore Hospital, Sydney, Australia.
Di Girolamo
Nick
N
Beck
Konstanze
K
Hanratty
Colm G
CG
Choy
Katherine
K
Hou
Jing Y
JY
Ward
Michael R
MR
Stocker
Roland
R
D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011341:Probucol / Q000494:pharmacology / Q000627:therapeutic use*; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis
D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D019010:Vascular Cell Adhesion Molecule-1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D011341:Probucol