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Aims Vascular calcification, a marker of increased cardiovascular risk, is an active process orchestrated by smooth muscle cells. Observational studies indicate that omega-3 fatty acids protect against vascular calcification, but the mechanisms are unknown. The G-protein coupled receptor ChemR23 transduces the resolution of inflammation induced by the omega-3-derived lipid mediator resolvin E1. ChemR23 also contributes to osteoblastic differentiation of stem cells and bone formation, but its role in vascular calcification is unknown. The aim of this study was to establish the role of ChemR23 in smooth muscle cell fate and calcification Methods and results Gene expression analysis in epigastric arteries derived from patients with chronic kidney disease and vascular calcification revealed that ChemR23 mRNA levels predicted a synthetic smooth muscle cell phenotype. Genetic deletion of ChemR23 in mice prevented smooth muscle cell de-differentiation. ChemR23-deficient smooth muscle cells maintained a non-synthetic phenotype and exhibited resistance to phosphate-induced calcification. Moreover, ChemR23-deficient mice were protected against vitamin D3-induced vascular calcification. Resolvin E1 inhibited smooth muscle cell calcification through ChemR23. Introduction of the Caenorhabditis elegans Fat1 transgene, leading to an endogenous omega-3 fatty acid synthesis and hence increased substrate for resolvin E1 formation, significantly diminished the differences in phosphate-induced calcification between ChemR23+/+ and ChemR23−/− mice. Conclusion This study identifies ChemR23 as a previously unrecognized determinant of synthetic and osteoblastic smooth muscle cell phenotype, favouring phosphate-induced vascular calcification. This effect may be of particular importance in the absence of ChemR23 ligands, such as resolvin E1, which acts as a calcification inhibitor under hyperphosphatic conditions. [ABSTRACT FROM AUTHOR]

Background: The immune cell response in atherosclerotic plaques is characterized by an impaired resolution of inflammation (1). Resolvin E1 (RvE1), a specialized pro-resolving lipid mediator derived from omega-3 polyunsaturated fatty acids (PUFA) has been shown to play a critical role in atherosclerosis by promoting the resolution of the inflammation (2). The aim of the present study was to unravel the role of omega-3 PUFA, RvE1 and the RvE1 receptor ChemR23 in the process of atherosclerotic plaque calcification. Methods: Fat-1 transgene (Fat-1tg), which enables the endogenous production of n-3 PUFA, was inserted in apolipoprotein E (ApoE)-deficient mice, in combination or not with genetic deletion of ChemR23. Calcification was assessed by Alizarin Red staining and macrophage markers were assessed by immunohistochemistry in aortic root sections. Results: Our results show that 72 week old Fat-1tg × Apoe-/- mice developed less atherosclerotic plaque calcification compared with Apoe-/- mice (0-3% vs 4-8%, p < 0.001). Moreover, deletion of ChemR23 enhanced atherosclerotic plaque calcification (4-13% vs. 4-8%, p < 0.001), and this effect was not reversed by the presence of Fat-1tg (4-14% vs. 4-8%, p < 0.001). Furthermore, the Fat- 1tg × Apoe-/- mice had significantly higher expression of the M2 macrophage marker Arg1 compared with Apoe-/- mice (17.4 ± 2.5% vs 5.1 ± 1.5%; p < 0.0001), which was reversed by genetic deletion of ChemR23 (5.0 ± 1.1% vs. 17.4 ± 2.5%; p < 0.0001 vs Fat-1tg × Apoe-/- mice). Conclusion: These results suggest that the beneficial effects of Fat- 1tg were mediated through ChemR23. Hence, omega-3 PUFA may have a therapeutic potential for reducing atherosclerotic plaque calcification through RvE1-signaling by means of ChemR23. [ABSTRACT FROM AUTHOR]

Aims Atherosclerosis is a chronic inflammatory disease that is initiated by the retention and accumulation of low-density lipoprotein in the artery, leading to maladaptive response of cells from the immune system and vessel wall. Strong evidence implicates indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of the kynurenine pathway of tryptophan (Trp) degradation, with immune regulation and anti-inflammatory mechanisms in different diseases. However, the role of IDO and the endogenous degradation of Trp have never been directly examined in atherosclerosis development. We used the IDO inhibitor 1-methyl-Trp (1-MT) to determine the role of IDO-mediated Trp metabolism in vascular inflammation and atherosclerosis. Methods and results Apoe-/- micewere treated with 1-MT in drinkingwater for 8weeks. Systemic IDO inhibition led to a significant increase in atherosclerotic lesions that were ∼58 and 54% larger in the aortic arch and root, respectively. 1-MT treatment enhanced vascular inflammation, up-regulated VCAM-1 and CCL2, and increased CD68 macrophage accumulation into the plaque. Notably, the rise in VCAM-1 expression was not limited to the plaque but also found in smooth muscle cells (SMCs) of the tunica media. Furthermore,we found that IDO-dependent Trp metabolism bySMCs regulates VCAM-1 expression, and that 1-MT-induced acceleration of atherosclerosis and vascular inflammation can be reversed by exogenous administration of the Trp metabolite 3-hydroxyanthranilic acid (3-HAA). Conclusion IDO-mediated Trp metabolism regulates vascular inflammation and plaque formation in hypercholesterolaemic Apoe-/- mice. Our data establish that this pathway plays a major role in the pathological process of atherogenesis. [ABSTRACT FROM AUTHOR]

Aims: Vascular calcification, a marker of increased cardiovascular risk, is an active process orchestrated by smooth muscle cells. Observational studies indicate that omega-3 fatty acids protect against vascular calcification, but the mechanisms are unknown. The G-protein coupled receptor ChemR23 transduces the resolution of inflammation induced by the omega-3-derived lipid mediator resolvin E1. ChemR23 also contributes to osteoblastic differentiation of stem cells and bone formation, but its role in vascular calcification is unknown. The aim of this study was to establish the role of ChemR23 in smooth muscle cell fate and calcification., Methods and Results: Gene expression analysis in epigastric arteries derived from patients with chronic kidney disease and vascular calcification revealed that ChemR23 mRNA levels predicted a synthetic smooth muscle cell phenotype. Genetic deletion of ChemR23 in mice prevented smooth muscle cell de-differentiation. ChemR23-deficient smooth muscle cells maintained a non-synthetic phenotype and exhibited resistance to phosphate-induced calcification. Moreover, ChemR23-deficient mice were protected against vitamin D3-induced vascular calcification. Resolvin E1 inhibited smooth muscle cell calcification through ChemR23. Introduction of the Caenorhabditis elegans Fat1 transgene, leading to an endogenous omega-3 fatty acid synthesis and hence increased substrate for resolvin E1 formation, significantly diminished the differences in phosphate-induced calcification between ChemR23+/+ and ChemR23-/- mice., Conclusion: This study identifies ChemR23 as a previously unrecognized determinant of synthetic and osteoblastic smooth muscle cell phenotype, favouring phosphate-induced vascular calcification. This effect may be of particular importance in the absence of ChemR23 ligands, such as resolvin E1, which acts as a calcification inhibitor under hyperphosphatic conditions., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)