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Int. J. Mol. Sci. 2017, 18(12), 2721; https://doi.org/10.3390/ijms18122721

Sphingosine-1-Phosphate Receptor 1, Expressed in Myeloid Cells, Slows Diet-Induced Atherosclerosis and Protects against Macrophage Apoptosis in Ldlr KO Mice

Department of Biochemistry and Biomedical Sciences, and Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, ON L8L 2X2, Canada
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Received: 23 November 2017 / Revised: 8 December 2017 / Accepted: 8 December 2017 / Published: 15 December 2017
(This article belongs to the Special Issue Sphingolipids: Signals and Disease)
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Abstract

We generated myeloid specific sphingosine-1-phosphate receptor 1 (S1pr1) deficient mice by crossing mice that had myeloid specific expression of Cre recombinase (lyzMCre) with mice having the S1pr1 gene flanked by loxP recombination sites. We transplanted bone marrow from these mice and control lyzMCre mice with intact macrophage S1pr1 gene expression into low-density lipoprotein (LDL) receptor gene (Ldlr) deficient mice. The resulting chimeras were fed a high fat atherogenic diet for nine or twelve weeks and evaluated for atherosclerosis development in the aortic sinus. Selective S1pr1 deficiency in bone marrow-derived myeloid cells resulted in accelerated development of atherosclerosis, necrotic core formation and the appearance of apoptotic cells within atherosclerotic plaques of Ldlr knockout mice in response to a high fat diet. Examination of macrophages in culture revealed that the sphingosine-1-phosphate receptor 1 selective agonist, SEW2871 or high density lipoprotein (HDL), protected macrophages against apoptosis induced by endoplasmic reticulum (ER) stress or oxidized LDL, through activation of phosphatidylinositol-3-kinase/Akt signaling. Targeted S1pr1-deletion prevented Akt activation and protection against apoptosis by either SEW2871 or HDL. Our data suggests that sphingosine-1-phosphate receptor 1 in macrophages plays an important role in protecting them against apoptosis in vitro and in atherosclerotic plaques in vivo, and delays diet induced atherosclerosis development in Ldlr deficient mice. View Full-Text
Keywords: apoptosis; atherosclerosis; HDL; macrophage; mouse model; sphingosine-1-phosphate receptor 1 apoptosis; atherosclerosis; HDL; macrophage; mouse model; sphingosine-1-phosphate receptor 1
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Gonzalez, L.; Qian, A.S.; Tahir, U.; Yu, P.; Trigatti, B.L. Sphingosine-1-Phosphate Receptor 1, Expressed in Myeloid Cells, Slows Diet-Induced Atherosclerosis and Protects against Macrophage Apoptosis in Ldlr KO Mice. Int. J. Mol. Sci. 2017, 18, 2721.

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