Probucol decreases neointimal formation in a swine model of coronary artery balloon injury. A possible role for antioxidants in restenosis.

Schneider, Joel E.; Berk, Bradford C.; Gravanis, Michael B.; Santoian, Edward C.; Cipolla, Gustavo D.; Tarazona, Norman; Lassègue, Bernard; King, Spencer B.

doi:10.1161/01.cir.88.2.628

Cited by 139 publications

(64 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Probucol is an anti-oxidant and lipid-reducing drug that has been in clinical use during the past few decades for the prevention and treatment of cardiovascular diseases. In experimental and clinical studies, probucol has been reported to reduce intimal proliferation following balloon injury in animals [12,13] and to inhibit restenosis after coronary angioplasty with [14] and without [15] stent in humans. Probucol also dramatically retards atherosclerosis in hyperlipidemic animals [16][17][18] .…”

Section: Original Articlementioning

confidence: 99%

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

et al. 2016

View full text Add to dashboard Cite

Aim: Increasing evidence suggests that probucol, a lipid-lowering agent with anti-oxidant activities, may be useful for the treatment of ischemic stroke with hyperlipidemia via reduction in cholesterol and neuroinflammation. In this study we examined whether probucol could protect against brain ischemic injury via anti-neuroinflammatory action in normal and hyperlipidemic mice. Methods: Primary mouse microglia and murine BV2 microglia were exposed to lipopolysaccharide (LPS) for 3 h, and the release NO, PGE2, IL-1β and IL-6, as well as the changes in NF-κB, MAPK and AP-1 signaling pathways were assessed. ApoE KO mice were fed a high-fat diet containing 0.004%, 0.02%, 0.1% (wt/wt) probucol for 10 weeks, whereas normal C57BL/6J mice received probucol (3, 10, 30 mg·kg -1 ·d -1 , po) for 4 d. Then all the mice were subjected to focal cerebral ischemia through middle cerebral artery occlusion (MCAO). The neurological deficits were scored 24 h after the surgery, and then brains were removed for measuring the cerebral infarct size and the production of pro-inflammatory mediators. Results: In LPS-treated BV2 cells and primary microglial cells, pretreatment with probucol (1, 5, 10 μmol/L) dose-dependently inhibited the release of NO, PGE2, IL-1β and IL-6, which occurred at the transcription levels. Furthermore, the inhibitory actions of probucol were associated with the downregulation of the NF-κB, MAPK and AP-1 signaling pathways. In the normal mice with MCAO, preadministration of probucol dose-dependently decreased the infarct volume and improved neurological function. These effects were accompanied by the decreased production of pro-inflammatory mediators (iNOS, COX-2, IL-1, IL-6). In ApoE KO mice fed a high-fat diet, pre-administration of 0.1% probucol significantly reduced the infarct volume, improved the neurological deficits following MCAO, and decreased the total-and LDL-cholesterol levels. Conclusion: Probucol inhibits LPS-induced microglia activation and ameliorates cerebral ischemic injury in normal and hyperlipidemic mice via its anti-neuroinflammatory actions, suggesting that probucol has potential for the treatment of patients with or at risk for ischemic stroke and hyperlipidemia.

show abstract

Section: Original Articlementioning

confidence: 99%

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

et al. 2016

View full text Add to dashboard Cite

show abstract

“…9 Probucol may also decrease vascular superoxide production, leading to improved endothelial function. 10 Probucol promotes positive adventitial remodeling after balloon angioplasty in humans, 11 and it inhibits intimal thickening after balloon injury in swine coronary 12 and in rabbit and rat carotid arteries independently of lowering cholesterol. 13,14 In addition, probucol inhibits the proliferation of vascular smooth muscle cells (VSMCs) in vivo 15 and in vitro, 16 whereas it promotes the proliferation of endothelial cells in vitro.…”

mentioning

confidence: 99%

Probucol Promotes Functional Reendothelialization in Balloon-Injured Rabbit Aortas

et al. 2003

View full text Add to dashboard Cite

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, 1.10Ϯ0.08 versus P, 0.70Ϯ0.10; normal: C, 0.89Ϯ0.02 versus P, 0.83Ϯ0.05; PϽ0.05) 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, PϽ0.05) and in those on normal chow (37% increase, PϽ0.01). 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.

show abstract

“…Its overall effects, however, remain somewhat contentious. Probucol commonly inhibits atherogenesis in hypercholesterolemic rabbits 12,13 and nonhuman primates 14 ; inhibits intimal thickening and restenosis after angioplasty in rabbits, 15 pigs, 16 and humans 17 ; and reverses established plaques in rabbits 18 and xanthomas in humans. 19 However, in cholesterol-fed rabbits maintained at comparable plasma cholesterol levels, probucol does not attenuate atherosclerosis.…”

mentioning

confidence: 99%

Site-Specific Antiatherogenic Effect of Probucol in Apolipoprotein E–Deficient Mice

Witting

Pettersson

Letters

et al. 2000

ATVB

View full text Add to dashboard Cite

Abstract-The lipid-lowering antioxidant probucol can inhibit atherosclerosis in animals and restenosis in humans.However, probucol has been shown to promote atherosclerosis in the aortic root of apolipoprotein E-deficient (apoEϪ/Ϫ) mice. In the current study, we examined the effects of probucol on both lesion formation at 4 sites along the aorta and lipoprotein oxidation in the plasma and aortas of apoEϪ/Ϫ mice receiving a diet containing 21.2% (wt/wt) fat and 0.15% (wt/wt) cholesterol without or with 1% (wt/wt) probucol. After 6 months, controls had developed lesions at all sites investigated. Lesion development was strongly (Pϭ0.0001) affected by probucol, but this effect was not uniform: lesion size was increased in the aortic root but significantly decreased in the arch, the descending thoracic aorta, and proximal abdominal aorta. Plasma and aortas of probucol-treated mice contained high concentrations of probucol and its metabolites (bisphenol and diphenoquinone); increased vitamin C; markedly decreased very low density lipoprotein (but not low density lipoprotein and high density lipoprotein); and decreased cholesterol, cholesteryl esters, triglycerides, vitamin E, and oxidized lipids compared with controls. Interestingly, probucol treatment did not decrease the proportion of aortic lipids that were oxidized. Plasma vitamin C and bisphenol, but not probucol, protected plasma lipids from ex vivo oxidation by peroxyl radicals. These results show that as in other species, probucol can inhibit lesion formation in most parts of the aorta of apoEϪ/Ϫ mice. This effect may involve lipid oxidation-independent mechanisms localized within the vessel wall as well as lipid lowering.

show abstract

Probucol decreases neointimal formation in a swine model of coronary artery balloon injury. A possible role for antioxidants in restenosis.

Abstract: The major finding of this study is that the antioxidant drug probucol reduces neointimal formation after oversized balloon injury in a swine model of restenosis. This suggests that active oxygen species may play a role in restenosis.

Cited by 139 publications

References 40 publications

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

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

Probucol Promotes Functional Reendothelialization in Balloon-Injured Rabbit Aortas

Site-Specific Antiatherogenic Effect of Probucol in Apolipoprotein E–Deficient Mice

Contact Info

Product

Resources

About