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Chronic inflammation is a hallmark of atherosclerosis and results from an imbalance between proinflammatory and proresolving signaling. The human GPR32 receptor, together with the ALX/FPR2 receptor, transduces biological actions of several proresolving mediators that stimulate resolution of inflammation. However, since no murine homologs of the human GPR32 receptor exist, comprehensive in vivo studies are lacking. Using human atherosclerotic lesions from carotid endarterectomies and creating a transgenic mouse model expressing human GPR32 on a Fpr2xApoE doubleKO background ([hGPR32.sub.myc] * [Fpr.sup.2-/-] * [Apoe.sup.-/-]), we investigated the role of GPR32 in atherosclerosis and self-limiting acute inflammation. GPR32 mRNA was reduced in human atherosclerotic lesions and correlated with the immune cell markers ARG1, NOS2, and FOXP3. Atherosclerotic lesions, necrotic core, and aortic inflammation were reduced in [hGPR32.sub.myc]Tg * [Fpr2.sup.-/-] * [Apoe.sup.-/-] transgenic mice as compared with [Fpr2.sup.-/-] * [Apoe.sup.-/-] nontransgenic littermates. In a zymosan-induced peritonitis model, the [hGPR32.sub.myc]Tg * [Fpr2.sub.-/-] * [Apoe.sub.-/-] transgenic mice had reduced inflammation at 4 hours and enhanced proresolving macrophage responses at 24 hours compared with nontransgenic littermates. The GPR32 agonist aspirin-triggered resolvin D1 (AT-RvD1) regulated leukocyte responses, including enhancing macrophage phagocytosis and intracellular signaling in [hGPR32.sub.myc]Tg * [Fpr2.sup.-/-] * [Apoe.sup.-/-] transgenic mice, but not in [Fpr2.sup.-/-] * [Apoe.sup.-/-] nontransgenic littermates. Together, these results provide evidence that GPR32 regulates resolution of inflammation and is atheroprotective in vivo., Introduction Resolution of acute inflammation is an active, coordinated response aimed at terminating the inflammatory response and restoring tissue homeostasis (1). Resolution of inflammation is regulated by a superfamily of [...]

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: 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.)