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  • These observations are of particular interest in the context


    These observations are of particular interest in the context of recent conceptual changes regarding the mechanisms by which different types of leukocytes contribute to atherogenesis. Over the last decade, the paradigm of the predominant circulatory origin of lesional macrophages has been challenged by the characterization of several effects that take place within the plaque, including macrophage proliferation [5], vascular smooth muscle cell (VSMC) transdifferentiation to macrophages [6], and macrophage polarization [7].
    Materials and Methods
    Discussion Recent advances in atherosclerosis research in the field of mechanistic cellular pathobiology indicate the need to revise the classical paradigms of the cellular mechanisms of atherogenesis. For instance, the commonly accepted notion that lesional macrophages and media-derived VSMC exhibit contrary characteristics in terms of plaque stability needs to be reevaluated, in view of discoveries from VSMC tracing studies [6]. New developments have evidenced a high degree of plasticity of macrophages and VSMC within the plaque, showing that macrophages respond to changes in their extra- and intracellular environment by giving rise to specific phenotypes [9], as 680C91 well as that macrophage-like 680C91 can differentiate from smooth muscle cells and, intriguingly, vice versa [6,10]. The main finding of our study is that activation of FFARs by GW9508 led to the reduction of atheroscletoric plaque size in an apoE-knockout mice model. Importantly, the FFAR1/FFAR4 agonist led to qualitative modifications in cellular lesion composition, reducing the content of macrophages by almost 20%. Detailed immunohistochemical evaluation of plaque composition, supported by molecular measurements, indicated that pro-inflammatory M1-like activation state macrophages (F4/80-iNOS positive cells) were significantly reduced in GW9508-treated apoE-/- mice. Our study is the first to describe the effects of GW9508 administration in an apoE-knockout experimental model. The discrepancy between the effect of FFAR1/FFAR4 agonist on macrophages at different activation states assessed in our study can be explained by the expression level of FFAR receptors in these populations. The FFAR4 induction has been attributed specifically to the M1-like phenotype, while the FFAR1 expression level on macrophages is low [2]. Moreover, whereas FFAR4 has been linked to the reduction of pro-inflammatory activation of macrophages, the anti-inflammatory effects of FFAR1 remain obscure [2]. It should be noted that our results are in line with the study of Matsumoto et al., which described the reduction of aortic lipid deposition and plaque macrophage content, accompanied by the elevation of the plaque collagen deposits in apoE-knockout model administered eicosapentaeonic acid (EPA), which is a known activator of FFAR4 [11]. Although challenged by some recent data [12], the beneficial cardiovascular effects of polyunsaturated fatty acids (PUFAs) are widely accepted. There is a growing body of evidence from both animal and human studies that PUFAs hold moderate anti-atherogenic potential [13]. Several general mechanisms of the action of PUFAs have been proposed to date, including stabilization of the vulnerable plaque, reduction of platelet aggregation, the lowering of plasma TG levels, or decreased infiltration of immune cells into the plaque [14]. On the molecular level, PUFAs have been proposed to inhibit toll-like receptors, activate peroxisome proliferation activator receptor gamma (PPARγ), or compete with arachidonic acid as a substrate for the major inflammatory enzymes of the eicosanoid pathway (cyclooxygenase 2, lipoxygenases), resulting in the synthesis of pro-resolving mediators (resolvins, protectins, maresins) [14]. For instance, it has been demonstrated that the synthesis of chemoattractant leukotriene B4 can be reduced by PUFAs, and such action may lead to a decrease in the recruitment of leukocytes to the lesions [14]. Moreover, PUFAs could reduce the expression of chemokine receptors on leukocytes, which further attenuates plaque infiltration [15]. It is noteworthy that the key hallmark of inflammation – activation of the NF-κB transcription factor pathway – is perturbed in the presence of PUFAs, and in macrophages this action has been directly attributed to FFAR4 activation [2]. Indeed, PUFAs are responsible for several important downstream, anti-atherogenic consequences of NF-κB inhibition, including a decrease in the production of cytokines and the expression of adhesion molecules on the surface of different cell types contributing to atherosclerotic plaque formation, including endothelial cells, monocytes, and macrophages [16,17].