Probucol Promotes Functional Reendothelialization in Balloon-Injured Rabbit Aortas

Lau, A.; Leichtweis, S.; Hume, Peter; Mashima, Ryuichi; Hou, Jing; Chaufour, Xavier; Wilkinson, Brendan L.; Hunt, Nicholas H.; Celermajer, David S.; Stocker, Roland

doi:10.1161/01.cir.0000062682.40051.43

Cited by 94 publications

(89 citation statements)

References 44 publications

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“…32 We are presently investigating whether the apparent antiinflammatory action of probucol is related to its ability to induce heme oxygenase-1. 17,18,33 Unexpectedly, we observed the extent of probucol metabolism to be significantly increased in the aorta compared with the sinus (Figure 4), suggesting that some of the differences in action at the sinus versus descending aorta may be related to probucol metabolism. We do not know at present whether this relates to the previously reported antiinflammatory activity of probucol, ie, inhibition of lipopolysaccharideinduced secretion of interleukin-1 by macrophages.…”

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confidence: 77%

Processes Involved in the Site-Specific Effect of Probucol on Atherosclerosis in Apolipoprotein E Gene Knockout Mice

Choy

Beck

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et al. 2005

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Objective-To elucidate processes by which the antioxidant probucol increases lesion size at the aortic sinus and decreases atherosclerosis at more distal sites in apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice. Methods and Results-Male apoEϪ/Ϫ mice were fed high-fat chow with 1% (w/w) probucol or without (controls) for 6 months, before aortic sinus, arch, and descending aorta were analyzed separately for lesion size and composition. Compared with control, probucol significantly increased lesion size by 33% at the sinus, but it inhibited atherosclerosis at the descending aorta by 94%. Sites where atherosclerosis was inhibited contained substantially fewer macrophages, less lipids (cholesterol and cholesteryl esters), and endogenous antioxidant (␣-tocopherol), but not oxidized lipids, and the extent to which probucol metabolism occurred was increased. Compared with control, aortic sinus lesions of probucol mice contained a substantially increased content of extracellular matrix, but decreased total cell and macrophage density, comparable levels of lipids and ␣-tocopherol, and decreased concentrations of oxidized lipids (cholesteryl ester hydroperoxides, F 2 -isoprostanes, and 7-ketocholesterol). Conclusions-Probucol affects atherosclerosis in apoEϪ/Ϫ mice independent of the accumulation of arterial lipid oxidation products, thereby dissociating the 2 processes. Rather, probucol exerts antiinflammatory activity by decreasing accumulation of macrophages in lesions, and it promotes a more stable lesion composition at the aortic sinus. Key Words: antioxidants Ⅲ atherosclerosis Ⅲ collagen Ⅲ free radicals Ⅲ inflammation A therosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. 1 The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in and that oxidized LDL contributes to atherogenesis. 2 Oxidized LDL supports foam cell formation in vitro and other potentially pro-atherogenic activities, the lipid in human lesions is oxidized and contains oxidized LDL, and several different antioxidants inhibit atherosclerosis in animals. 1 In addition to LDL oxidation, other relevant oxidative events include the production of reactive oxygen and nitrogen species by vascular cells, 3 and oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. 1 However, despite abundant data, fundamental problems remain with implicating oxidative modification as a requisite cause for atherosclerosis. 1 These include the poor performance of antioxidants in limiting atherosclerosis or cardiovascular events from it, 4 and observations in animals that suggest dissociation between atherosclerosis and lipoprotein lipid oxidation. [5][6][7][8][9] To reconcile these discrepancies, the "oxidative response to inflammation" model of atherosclerosis 1 considers inflammation as a primary process of atherosclerosis, an...

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confidence: 77%

Processes Involved in the Site-Specific Effect of Probucol on Atherosclerosis in Apolipoprotein E Gene Knockout Mice

Choy

Beck

Png

et al. 2005

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“…Rabbits received normal chow (control) or chow supplemented with probucol (1%, w/w), DTBP (0.2%), or BP (0.02%) as described previously (31); these concentrations resulted in comparable drug levels in the aortas of supplemented animals. Feed and water were provided ad libitum for a period of 4 weeks judged to be sufficient time for circulating drug levels to reach a maximum (data not shown).…”

Section: Methodsmentioning

confidence: 99%

“…Vascular Reactivity-Perfused rabbit aortas were harvested and vascular reactivity studies performed as described (31). Briefly, within 2 h of isolation, ring segments ϳ5 mm in length were mounted in a myobath system (World Precision Instruments, Sarasota, FL) containing 20 ml of Krebs solution aerated at 37°C with 5% CO 2(g) , and the dilatory response of half-maximally norepinephrine preconstricted rings to incremental doses of acetylcholine (10…”

Section: Methodsmentioning

confidence: 99%

Probucol Protects against Hypochlorite-induced Endothelial Dysfunction

Witting

Raftery

et al. 2005

Journal of Biological Chemistry

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Atherosclerosis is associated with endothelial dysfunction and a heightened state of inflammation characterized, in part, by an increase in vascular myeloperoxidase and proteins modified by its principal oxidant, hypochlorous acid (HOCl). Here we examined whether probucol could protect against endothelial dysfunction induced by the two-electron oxidant HOCl. Hypochlorous acid eliminated endothelium-dependent relaxation of rabbit aorta, whereas endothelial function and tissue cGMP was preserved and elevated, respectively, in animals pretreated with probucol. Exogenously added probucol also protected against HOClinduced endothelial dysfunction. In vitro, HOCl oxidized probucol in a two-phase process with rate constants k 1 ‫؍‬ 2.7 ؎ 0.3 ؋ 10 2 and k 2 ‫؍‬ 0.7 ؎ 0.2 ؋ 10 2 M ؊1 s ؊1 that resulted in a dose-and time-dependent accumulation of probucolderived disulfoxide, 4,4-dithiobis(2,6-di-tert-butyl-phenol) (DTBP), DTBP-derived thiosulfonate, disulfone, and sulfonic acid, together with 3,3,5,5-tetra-tert-butyl-4,4-diphenoquinone (DPQ) as determined by high performance liquid chromatography and mass spectrometry. Like HOCl, selected one-electron oxidants converted probucol into DTBP and DPQ. Also, dietary and in vitro added DTBP protected aortic rings from HOCl-induced endothelial dysfunction and in vitro oxidation by HOCl gave rise to the thiosulfonate, disulfone, and sulfonic acid intermediates and DPQ. However, the product profiles of the in vitro oxidation systems were different from those in aortas of rabbits receiving dietary probucol or DTBP ؎ HOCl treatment. Together, the results show that both probucol and DTBP react with HOCl and protect against HOClinduced endothelial dysfunction, although direct scavenging of HOCl is unlikely to be responsible for the vascular protection by the two compounds.

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“…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

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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.

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Probucol Promotes Functional Reendothelialization in Balloon-Injured Rabbit Aortas

Cited by 94 publications

References 44 publications

Processes Involved in the Site-Specific Effect of Probucol on Atherosclerosis in Apolipoprotein E Gene Knockout Mice

Processes Involved in the Site-Specific Effect of Probucol on Atherosclerosis in Apolipoprotein E Gene Knockout Mice

Probucol Protects against Hypochlorite-induced Endothelial Dysfunction

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

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