Resveratrol and foam cell formation

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We have seen previously that oxLDLs favor the transformation of macrophages into foam cells [48]. The development of macrophage foam cells that contain massive amounts of cholesterol ester is a hallmark of both early and late atherosclerotic lesions. OxLDL derived cholesterol brought into the macrophage via scavenger receptors consists of free cholesterol as well as cholesterol esters that are hydrolyzed in lysosomes. In addition, oxLDLs stimulate ECs to produce chemokines, granulocyte and macrophage colony-stimulating factors [49] and they have direct chemotactic activity for monocytes to endothelium [50]. Resveratrol contributes to reduce the production of chemokines which may be responsible for the chemotaxis and accumulation of macrophages in fatty streaks (figure 3). Resveratrol is able to inhibit interleukin-6 (IL-6) release by stimulated peritoneal macrophages in mice [51, 52], and in cortical mixed glial cells [53]. This action could result from a calcium blocking of calcium ion influx by resveratrol (see further “resveratrol and platelet aggregation”). Moreover, resveratrol contributes to reduce inflammatory response in atherosclerosis when macrophages (or SMC, EC) appear to be activated and produce numerous inflammatory products, such as TNFa, IL-6, monocyte chemoattractant protein-1 (MCP-1) (figure 3). Lesion progression is influenced by interactions between monocyte/macrophage and T cells. Lesional T cells appear to be activated, expressing both Th1 and Th2 cytokines [54] (figure 4). Resveratrol was able to inhibit the release of Th1-derived cytokines such as interferon g (INFg) which stimulates macrophage production of pro-inflammatory cytokines, IL-2 production by splenic lymphocytes and TNF-a and IL-12 production by peritoneal macrophage [55-57] (figure 4). The expression of mRNA encoding MCP-1 was also blocked by resveratrol [58]. Resveratrol was also able to inhibit Th2-derived cytokines such as IL-4 which exerts antagonistic effects on INFg activity in macrophages and inhibition of Th1 cell function. Resveratrol inhibits the LPS-induced expression of IL-1mRNA in monocytes and ECs [59]. Concerning IL-8, the gene transcription as well as the protein production are inhibited by resveratrol [60].

This inhibition of cytokines production by the resveratrol is important for the regulation of adhesion molecule expression. Indeed, activated T lymphocytes and macrophages generate and release several cytokines with a number of biological effects on neighbouring cells [61]. So, various proinflammatory stimuli (e.g. interleukins, INFg, TNFa, LPS) induce the expression of vascular adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1). These molecules mediate the firm adhesion of monocytes to the vascular endothelium in early atherosclerosis stages (figure 2 ou 3). Like others compounds of tyrphostine family which possess tyrosine kinase inhibitory activity [62, 63], resveratrol inhibits both the stimulated expression of VCAM-1 and monocyte adhesion to human vascular endothelial cells [64, 65]. These effects also affect E-selectin and ICAM-1. Indeed, resveratrol decreased significantly the expression of ICAM-1 and VCAM-1 induced on endothelial cells by TNF-a or lipopolysaccharide (LPS) [66], as well as neutrophile and monocyte endothelial adhesion [67, 68]. This inhibition of adhesion molecule expression occurs at the same doses of resveratrol plasmatic concentrations ranging from 100 nmol/L to 1 µmol/L in rat [64, 69]. It has been suggested that resveratrol may act as a rapid molecular signal interfering in the mechanism of VCAM-1 and ICAM-1 expression [70]. Vascular ECs can also to activated by proteolytic enzymes such as elastase which cause detachment or lysis of ECs and degradation of subendothelial matrices [71] and stimulate EC secretion of growth factors for SMC [72]. Resveratrol inhibits the release of both elastase and b-glucuronidase by polymorphonuclear leukocytes stimulated by fMLP and C5a and also inhibits their secretion [40]. So this modification of adhesion by resveratrol may support its use as an immunomodulating compound.