Diphenyl Diselenide Effectively Reduces Atherosclerotic Lesions in LDLr −/− Mice by Attenuation of Oxidative Stress and Inflammation

Abstract

Glutathione peroxidase (GPx) plays an important role in the antioxidant defense of the vascular wall, and its deficiency has been implicated in the development of atherosclerotic lesions. This study analyzed the potential of diphenyl diselenide (DD), a simple organoselenium compound with GPx-like activity, to reduce atherosclerosis. Herein, we demonstrate that oral treatment with low doses of DD potently reduced the formation of atherosclerotic lesion in hypercholesterolemic low-density lipoprotein (LDL) receptor knockout (LDLr -/-) mice. This reduction was accompanied by significantly improved endothelium-dependent vasorelaxation, lower nitrotyrosine and malondialdehyde levels, decrease in vessel-wall infiltration by inflammatory cells, and prevention of upregulation of the proatherogenic monocyte chemoattractant protein-1. Studies in J774 macrophage-like cells show that DD significantly decreased oxLDL-induced formation of foam cells and the generation of reactive oxygen species and inflammatory mediators. Our results reveal the antiatherogenic actions of DD by modulating intracellular signaling pathways related to antioxidant and anti-inflammatory responses.

Anti-Atherogenic Effects of a Phenol-Rich Fraction from Brazilian Red Wine (Vitis labrusca L.) in Hypercholesterolemic Low-Density Lipoprotein Receptor Knockout Mice

“…Once the phenylephrine-induced contraction reached a steady state, vasodilating responses to cumulative increments in the concentration of acetylcholine (1 nM-3 lM) were examined. 25 …”

Enzymatic Targets in Atherosclerosis

“…The sooner pitfalls and misinterpretations will be detected, the better both for the benefit of people and to reduce the economic burden associated with death endclinical trials. Lp-PLA2 (-) Inhibition by RNAi [101] and selective inhibitors [102,103] reduced lipid accumulation and progression of coronary atherosclerosis in various atherogenic experimental models PCSK9 (-) Inhibition by alirocumarib reduced LDL levels [1] Oxidative stress related enzymes NADPH oxidase (-) NOX1/4 inhibitor GKT136901 reduced ROS [119,120]; NOX1/2 inhibitor apocynin reduced aortic lesions in apoE-/-LDLR-/-mice [121] Nitric Oxide Synthase (+) Adenovirus-mediated iNOS gene transfer studies showed that local NO synthesis induced significant proliferation of SMCs and intimal hyperplasia in rats [135] Superoxide dismutases (+) SOD local delivery decreased the cuff-induced arterial neointima [138], accelerated endothelial recovery and inhibited in-stent restenosis in the aorta of Watanabe rabbits [139]; mitochondrial SOD protected apoE-/-mice against atherosclerosis [140,141] Catalases (+) Overexpression retarded atherosclerosis development in apoE-/-mice [141]; dietary supplements upregulated CAT expression in apoE-/-mice and reduced atherosclerosis [144,145]; CAT attenuated non-dietary atherosclerosis in apoE-/-mice [146] Glutathione peroxidases (+) Mimetic diphenyl diselenide reduced atherosclerotic lesions in LDLR-/-mice [153] Heme oxygenase-1 (+) Inducers hemin±desferrioxamine reduced atherosclerotic lesions in LDLR-/-mice [164] Paraoxonases (+) Reduced protein N-homocysteinylation, prevented accumulation of oxLDL, promoted cholesterol efflux from macrophages [173], improved endothelial function [174] Vascular remodeling related enzymes Matrix Metalloproteases (-)/(+) Area of aortic calcified lesions was reduced in apoE-/-/MMP2-/-mice compared to apoE-/-mice ( [192]); apoE-/-/MMP-3-/-and apoE-/-/MMP-9-/-mice had larger brachiocephalic artery plaques [193], while lesion size was reduced in apoE-/-/MMP-12-/-mice [193] Inflammation related enzymes Cyclooxygenase (-) COX-1 knockout in apoE-/-mice reduced platelet-vascular wall interactions and decreased lesions [203] Lipoxygenase (-) 12/15 LO knockout in macrophages impaired oxLDL-induced foam cell formation and endothelial activation …”

“…In humans, decreased GPx-1 activity in red blood cell was found to be related to multivascular atherosclerosis and an augmented cardiovascular risk [151]. Diphenyl diselenide, an organoselenium compound with GPx mimetic abilities was found to inhibit human LDL oxidation in vitro [152] and to reduce the formation of atherosclerotic lesions in hypercholesterolemic LDLR knockout mice [153]. Therefore, it is considered that diphenyl diselenide has antiatherogenic actions by modulating intracellular signaling pathways related to antioxidant and anti-inflammatory responses.…”

New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people?

“…Moreover, (PhSe)2 was shown to inhibit human LDL oxidation in vitro [45] , to reduce foam atherosclerotic lesion in hypercholesterolemic LDL receptor knockout (LDLr -/-) mice, to decrease infiltration of inflammatory cells in vessel-wall, and to prevent the upregulation of the proatherogenic monocyte chemoattractant protein-1 [47] . Recent results demonstrated that (PhSe)2 is able to increase HMGR phosphorylation/ inactivation and LDLr protein levels without directly inhibiting HMGR activity [1] .…”