Probucol Protects against Hypochlorite-induced Endothelial Dysfunction

Abstract

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.

Reactions of Myeloperoxidase-Derived Oxidants with Biological Substrates:Gaining Chemical Insight into Human Inflammatory Diseases

“…Thus it is likely that the slower oxidation step seen with probucol is due to the reaction of HOCl with the intermediate disulfide species, DTBP. The rate constant determined for this compound [139] is more than 3 orders of magnitude smaller than that determined for aliphatic disulfide groups (Table 1) [54,78]. This observation is readily explained by the delocalization of the sulfur lone-pair electrons into the aromatic rings of the phenol substituents, thereby dramatically reducing the nucleophilic nature of the sulfur residues.…”

“…Kinetic studies using ambiguous; these reactions are discussed in greater detail below. process, with the second-order rate constant identical to the slow step measured for probucol itself [139]. Thus it is likely that the slower oxidation step seen with probucol is due to the reaction of HOCl with the intermediate disulfide species, DTBP.…”

Succinobucol, a Lipid-Lowering Drug, Protects Against 3-Nitropropionic Acid-Induced Mitochondrial Dysfunction and Oxidative Stress in SH-SY5Y Cells via Upregulation of Glutathione Levels and Glutamate Cysteine Ligase Activity

“…5a). Taking into account that such an effect was observed when using low succinobucol concentration (3 μM) and relatively long-term pretreatment (6 days), and based on its presumable poor scavenger properties [35,67], it is reasonable to suppose that the beneficial effects of succinobucol in blunting 3-NP-induced increase of reactive species were not necessarily dependent upon its scavenging properties. In line with this, succinobucol pretreatment was able to significantly increase (50 %) the levels of GSH (Fig.…”

Specific Dietary Polyphenols Attenuate Atherosclerosis in Apolipoprotein E–Knockout Mice by Alleviating Inflammation and Endothelial Dysfunction

“…The synthetic phenol probucol and its metabolites can induce HO-1 and may be the main mode of action for the protective effects of this compound against atherosclerotic disease. 54,55 Interestingly, arterial induction of HO-1 can protect eNOS from oxidative inactivation, 62 and NO can induce HO-1, 63 so that the 2 pathways may interact with each other in providing protection against atherosclerosis by polyphenols and other compounds.…”