Resveratrol and oxidative stress

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The second important event in the lesion formation is LDLs oxidation in the intima [13, 14]. Lipid peroxidation is a chain reaction process which can be induced by different free-radical sources (ionizing irradiation, UV light). Several groups have reported that oxidized-LDL (ox-LDL) can stimulate platelet aggregation [15] or promote procoagulant activity in the surface of human monocytes / macrophages by an increase in tissue thromboplastin activity [16] or by stimulating the expression and secretion of the tissue factor (TF) by monocytes or aortic endothelial cells [17].

Frankel et al, were the first to demonstrate that resveratrol added to human LDL, reduced the oxidation of human LDL induced by ncubation with a heavy metal ion such as copper [18]. This effect should be assigned to the chelation of copper because metals act as pro-oxidants by electron transfer, releasing free radicals from polyunsaturated fatty acids and hydroperoxides. It has been demonstrated that resveratrol suppresses lipid peroxidation both by chelation of copper [19-21] and by scavenging of the free radicals [19, 20, 22]. The efficiency and action mechanism of trans-resveratrol have been demonstrated in the radical liposome oxidation where it appeared that para-hydroxyl group shows a greater radical-scavenging activity than meta-hydroxyl groups of trans-resveratrol [23]. Moreover, the spatial position of hydroxyl groups is likely more propitious to the chelation of copper in the trans isomer than in cis isomer [20]. Due to its hydroxylated structure, resveratrol can form a radical derivative stabilized by the delocalisation of two electrons between the two aromatic cycles and the methylene bridge joining these two cycles. In addition to metal ion induced oxidation of LDLs, various enzymatic systems presents in endothelial cells (ECs) or macrophages are implicated in the oxidation of LDL (figure 2). These systems include nicotinamide adenine dinucleotide (NADPH) oxidases, hypoxanthine / xanthine oxidase (HX/XO), 15-lipoxygenase (15-LO), myeloperoxidase (MPO) and nitric oxide synthases (NOS) [24, 25]. The products of these enzymes oxidize LDL which alter ECs, stimulate NADPH oxidase, the pro-inflammatory cytokines release, and inhibit endothelial nitric oxide synthase (eNOS) implicated in the vasorelaxation. So, resveratrol can act on these enzymes (figure 2).

NAD(P)H oxidases play an important role in superoxide production, O₂^.-, in human vessels. Many cytosolic regulatory proteins (e.g. Rac) play an important part in regulating NAD(P)H oxidase activity in cardiovascular disease states by acute activation of the enzyme complex [26]. Resveratrol reduces the strain-increased NAD(P)H oxidase activity and NAD(P)H oxidase activity in rat aortic homogenates [27]. The isomer cis-resveratrol inhibits also NAD(P)H oxidase activity in macrophage homogenate [28]. These effects contribute to reduce intracellular reactive oxygen species (ROS) formation in EC caused by strain treatment.

Resveratrol inhibits leukocyte adhesion induced by other superoxide-dependent stimuli such as HX/XO which metabolize hypoxanthine, xanthine, and NADH to form uric acid, O₂^.- and H₂O₂ and platelet-activating factor [29].

Resveratrol is able to induce cellular antioxidants and phase 2 enzymes, including superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione-S-transferase, gluthatione reductase, NADPH:quinone oxidoreductase [27, 29, 30]. These results are also found in vivo. These modifications contribute to increase the resistance to cardiac cell injury elicited by ROS.

Resveratrol reduced the generation of H₂O₂, and normalized the levels of oxidized- glutathione reductase and MPO activities [31, 32]. MPO seemed to be important in vascular pathology because it change H₂O₂ to hypochlorous acid (HOCl) and other oxidizing species (figure 3). It also utilizes NO to generate ROS, thereby reducing NO bioactivity and increasing oxidative stress. By the normalization of the ROS levels, resveratrol limits the oxidative stress which inhibits NO synthesis by eNOS necessary for vasorelaxation (figure 3).

Oxidation induced by endothelial cells or by macrophages depends on lipoperoxides generated intracellularly and then transferred to the LDL. Cellular lipoxygenases, especially 15-lipoxygenase, appear to be involved [33, 34]. Various studies demonstrated that resveratrol inhibits lipoxygenases, in particular in human neutrophils where resveratrol strongly inhibits the 5- and 15-lipoxygenases producing in the arachidonate metabolism various proinflammatory products [35-38].

In addition to metal ions and ROS, ferrylmyoglobin and peroxynitrite are also potent oxidants implicated in oxidation of LDLs. Resveratrol was able to decrease the accumulation of hydroperoxides in LDL promoted by ferromyoglobin by reduction of the oxoferryl complex to metmyoglobin. Moreover the polyphenol inhibits LDL apoprotein modifications induced by peroxynitrite [39]. ROS production by polymorphonuclear leukocytes stimulated with formyl methionyl leucyl phenyalanine (fMLP) can be also strongly inhibited by resveratrol [40].

Moreover, resveratrol could act on targets in blood cells and in lipoproteins. Indeed, resveratrol was incorporated into blood cells and lipoproteins after in vitro incubations with plasma, lipoproteins and cells [41]. In fact, due to its lipophilic character, resveratrol is able to bind the lipoprotein particles suggesting that this event improved its anti-oxidant activity [42]. In lipoprotein particles, resveratrol is predominantly associated with their lipid moiety, but can be also associated with the protein moiety. Among plasma proteins, serum albumin could be involved [43]. This binding could explain that resveratrol reduce the oxidative alterations of lipid and protein moieties of LDL [19]. By protecting apoB domains involved in the receptor activity of cells, resveratrol could reduce the non-specific uptake of oxLDL by macrophages.