Probucol Attenuates Inflammation and Increases Stability of Vulnerable Atherosclerotic Plaques in Rabbits

Abstract

Probucol, a lipid-lowering agent with anti-oxidant properties, has been implicated in protection against atherogenesis, whereas its effect on plaques stability remains to be fully elucidated. The present study was aimed to test the hypothesis that probucol may attenuate inflammation and increase stability of vulnerable atherosclerotic plaques using a rabbit model. After abdominal aortic balloon injury, 45 rabbits were fed a 1% cholesterol diet for 24 weeks. From week 12 to week 24, the animals were treated with probucol (1% by weight in the diet), simvastatin (5 mg·kg -1 , positive control) or no drugs (control), respectively. At the end of week 22, recombinant-p53 adenovirus was injected into the abdominal aortic plaques. Two weeks later, plaque disruption was induced by injection of Chinese Russell's viper venom and histamine. The results showed that the incidence of plaque disruption in probucol or simvastatin groups was significantly lower than that in the control group (7.15% or 14.29% vs. 71.43% respectively, both P < 0.01). Probucol significantly increased the thickness of fibrous caps and decreased plaque vulnerability index. Serum concentrations of inflammatory cytokines and matrix metalloproteinases, and expression levels of Toll-like receptor (TLR)-2, TLR-4, monocyte chemoattractant protein-1, intercellular adhesion molecule 1, scavenger receptor A, CD36 and oxidized low-density lipoprotein receptor 1 within the lesions were markedly lower in both treatment groups than in the control group. We conclude that probucol increases the stability of vulnerable plaques, possibly through its lipid lowering, anti-inflammation and scavenger receptors suppression effects, suggesting probucol as a promising pharmacologic approach to stabilize vulnerable plaques.

Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

“…Specifically, probucol has been found to have the capacity to inhibit the expression of oxidation-sensitive inflammatory factors, such as VCAM-1 [38] , MCP-1 [39] , and IL-1 [40] . Additionally, the serum concentrations of inflammatory cytokines (CRP, IL-6, IL-18, and TNF-α) are markedly lower in probucol-treated atherosclerotic rabbits [24] . The expression of TNF-α, TGF-β, and HSP70 is also significantly downregulated by probucol treatment in alloxaninduced diabetic rabbits [23] .…”

“…Therefore, the identification of novel agents that regulate neuroinflammation by inhibiting microglial activation is regarded as a significant strategy for the treatment of ischemic stroke. Several animal studies have demonstrated that probucol exerts beneficial effects via anti-inflammation mechanisms in aging mice [19,20] , focal cerebral ischemic mice [8,9] , heart failure rats [21,22] , diabetic rabbits [23] and atherosclerotic rabbits [24] . Probucol has also been demonstrated to prevent atherogenesis via the induction of the anti-inflammatory enzyme heme oxygenase-1 independently of lipid oxidation and cholesterol reduction in models of atherosclerosis, restenosis and type 2 diabetes [32] .…”

“…Probucol also dramatically retards atherosclerosis in hyperlipidemic animals [16][17][18] . Furthermore, probucol has been demonstrated to posse the capacity to attenuate inflammation in animal models of aging [19,20] , focal cerebral ischemia [8,9] and ischemic myocardial injury [21,22] , as well as in diabetic [23] and atherosclerotic rabbits [24] . Based on these reports, probucol may be useful for the treatment of ischemic stroke with hyperlipidemia via reductions in cholesterol and neuroinflammation.…”

Effects of Serum Lipid Smoothness on the Progression and Vulnerability of Atherosclerotic Plaques in Rabbits

“…The serum hs-CRP, IL-18, ET-1, OX-LDL and NO levels were measured with rabbit ELISA kits (Santa Cruz Biotechnology, Inc) as previously described in literature [5]–[7].…”

Probucol plus cilostazol attenuate hypercholesterolemia-induced exacerbation in ischemic brain injury via anti-inflammatory effects

“…Probucol is capable of inhibiting the expression of oxidation-sensitive inflammatory factors, such as VCAM-1 (41), MCP-1 (42) and IL-1 (43), and attenuating inflammation and increasing stability of vulnerable atherosclerotic plaques in rabbits (44). Serum concentrations of inflammatory cytokines and matrix metalloproteinases, and expression levels of the Toll-like receptor (TLR)-2, TLR-4, MCP-1, ICAM-1, scavenger receptor A, CD36 and oxidized LDL receptor 1 within the lesions were markedly decreased in probucol treatment groups as compared to the control group (44).…”