Resveratrol and macrophages

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In normal conditions, the monocytes enter, through diapedesis, the subendothelial space, where they differentiate into macrophages (figure 2). Under endothelial dysfunction, circulating monocytes adhere to the arterial endothelium, migrate to the subendothelial space, and differenciate into resident macrophages within the subendothelial matrix. OxLDL stimulate the expression of scavengers receptors CD36 and the class A scavenger receptor (SR-A) within monocytes, macrophages and smooth muscle cells (SMC) (which normally do not express this receptor). These receptors internalize the oxLDL in a specific manner, leading to a massive accumulation of cholesterol esters until foam cells are formed. These macrophage-derived foam cells make up the fatty streak that precedes more advanced sclerotic lesions (figure 2).

Oxidative stress caused by phorbol esters or reactive oxygen up-regulates the SR-A in human SMC, which normally do not express this receptor [44]. Resveratrol inhibits the activity and the expression of SMC cyclooxygenase-2 (COX-2) which normally produced prostaglandin E₂ (PGE₂) which up-regulate SR-A expression [44]. Various growth factors such as interleukin-1 (IL-1), tumor necrosis factor alpha (TNFa), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and transforming growth factor beta (TGFb) increase SMC SR-A activity [45]. Resveratrol could be able to decrease SMC SR-A activity through the action of these factors such as the decrease of EGF [46] (figure 2).

So, by the reduction of the interaction of oxLDL with macrophage scavenger receptors which play an atherogenic role, resveratrol contributes to prevent an early step in atherogenesis. At a molecular level, the acute formation of oxLDL-induced by ROS leads to the activation of mitogen-activated protein kinases (MAPK) pathways, which might be important for mitogenic signaling of oxLDL in VSMCs (see below figure 5). Resveratrol inhibits oxLDL-induced mitogenesis of VSMCs through the blocking of the ROS generation and the activation of the extracellular signal-regulated kinases (ERKs) pathway [47].