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.
Highlights
Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells in the walls of large- and medium-sized arteries [1]
Hla and co-workers reported that selective endothelial cell specific sphingosine-1-phosphate receptor 1 (S1pr1) KO induced in juvenile apolipoprotein E (ApoE) KO mice resulted in enhanced high fat (HF) diet-induced atherosclerosis [27]
We demonstrate that selective S1pr1 KO in bone marrow (BM)-derived myeloid cells accelerates the high-fat diet-induced development of atherosclerosis in LDL receptor gene knockout (Ldlr KO) mice
Summary
Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells in the walls of large- and medium-sized arteries [1]. In cultured macrophages, the S1PR1 selective agonist SEW2871 and high density lipoprotein (HDL; reported to be a major plasma carrier of S1P, the natural ligand for S1PR1) were able to protect primary mouse macrophages from apoptosis, and that this involved SEW2871- or HDL-induced activation of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway. Together, these results demonstrate that S1PR1 in macrophages may be an important mediator of HDL dependent protection against cellular apoptosis and plays a role in delaying apoptosis and necrotic core development within atherosclerotic plaques
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