Abstract:

Objective   The heme oxygenase-1 (HO-1) system of heme catabolism has been implicated in protection against atherosclerotic vascular diseases. This study was aimed to test the hypothesis that probucol could inhibit the progression and destabilization of plaques by induction of HO-1. Methods   Atherosclerotic plaques were induced in aortas of 60 male New Zealand white rabbits by an atherogenic diet for 12 weeks after endothelial injury. Rabbits were then randomly divided into 4 groups which received no treatment, probucol, Sn protoporphyrin IX (SnPP IX), or probucol plus SnPP IX for 12 weeks. Serological, pathological, immunohistochemical and gene expression studies were performed at the end of the 24th week. Results   Probucol significantly induced HO-1 mRNA, protein, and enzyme activity in atherosclerotic plaques. This induction was correlated with a reduction in the progression of plaque size. Furthermore,this induction resulted in features of plaque stability such as increasing fibrous cap thickness and less macrophage infiltration. Moreover, the serum levels of oxidized low density lipoprotein and pro-inflammatory factors, including matrix metalloproteinase-9, interleukin18 and high sensitive C-reactive protein were remarkably reduced by probucol(P<0.01). In contrast, inhibition of HO-1 by SnPP IX not only augmented plaque progression and vulnerability but also raised the serum levels of the oxidized and pro-inflammatory factors(P<0.01). So it significantly reduced the effects of probucol(P<0.01). Conclusions   Our results demonstrated that probucol treatment may inhibit atherosclerosis progression and promote plaque stability by induction of HO-1. HO- may be the target of probucol′s anti-atherosclerosis action.

Key words: Probucol; Heme oxygenase-1; Atherosclerosis