Sphingosine-1-phosphate receptor-2 deficiency leads to inhibition of macrophage proinflammatory activities and atherosclerosis in apoE-deficient mice
Fei Wang, … , Makoto Kinoshita, Yoh Takuwa
Fei Wang, … , Makoto Kinoshita, Yoh Takuwa
Published November 1, 2010; First published October 18, 2010
Citation Information: J Clin Invest. 2010;120(11):3979-3995. https://doi.org/10.1172/JCI42315.
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Research Article Cardiology

Sphingosine-1-phosphate receptor-2 deficiency leads to inhibition of macrophage proinflammatory activities and atherosclerosis in apoE-deficient mice

Abstract

Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that has pleiotropic effects in a variety of cell types including ECs, SMCs, and macrophages, all of which are central to the development of atherosclerosis. It may therefore exert stimulatory and inhibitory effects on atherosclerosis. Here, we investigated the role of the S1P receptor S1PR2 in atherosclerosis by analyzing S1pr2–/– mice with an Apoe–/– background. S1PR2 was expressed in macrophages, ECs, and SMCs in atherosclerotic aortas. In S1pr2–/–Apoe–/– mice fed a high-cholesterol diet for 4 months, the area of the atherosclerotic plaque was markedly decreased, with reduced macrophage density, increased SMC density, increased eNOS phosphorylation, and downregulation of proinflammatory cytokines compared with S1pr2+/+Apoe–/– mice. Bone marrow chimera experiments indicated a major role for macrophage S1PR2 in atherogenesis. S1pr2–/–Apoe–/– macrophages showed diminished Rho/Rho kinase/NF-κB (ROCK/NF-κB) activity. Consequently, they also displayed reduced cytokine expression, reduced oxidized LDL uptake, and stimulated cholesterol efflux associated with decreased scavenger receptor expression and increased cholesterol efflux transporter expression. S1pr2–/–Apoe–/– ECs also showed reduced ROCK and NF-κB activities, with decreased MCP-1 expression and elevated eNOS phosphorylation. Pharmacologic S1PR2 blockade in S1pr2+/+Apoe–/– mice diminished the atherosclerotic plaque area in aortas and modified LDL accumulation in macrophages. We conclude therefore that S1PR2 plays a critical role in atherogenesis and may serve as a novel therapeutic target for atherosclerosis.

Authors

Fei Wang, Yasuo Okamoto, Isao Inoki, Kazuaki Yoshioka, Wa Du, Xun Qi, Noriko Takuwa, Koichi Gonda, Yasuhiko Yamamoto, Ryunosuke Ohkawa, Takumi Nishiuchi, Naotoshi Sugimoto, Yutaka Yatomi, Kunitoshi Mitsumori, Masahide Asano, Makoto Kinoshita, Yoh Takuwa

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Figure 1

Decreased atherogenesis in mice lacking S1PR2.

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Decreased atherogenesis in mice lacking S1PR2. (A and B) Representative ...
(A and B) Representative oil red O staining of spread aortas from S1pr2+/+Apoe–/– (n = 13) and S1pr2–/–Apoe–/– (n = 12) mice (N3 generation) after 8 and 16 weeks of HCD (A) and S1pr2+/+Apoe–/– (n = 11), S1pr2+/–Apoe–/– (n = 7), and S1pr2–/–Apoe–/– mice (n = 5) (N7 generation) after 16 weeks of HCD (B). Quantification of plaque areas is shown (right). *P < 0.05; **P < 0.01. (C–H) Histological analysis of the sections of the aortas from S1pr2+/+Apoe–/– and S1pr2–/–Apoe–/– mice (N3 generation). Oil red O staining (C); Azan staining (D); immunostaining of Mac-3 (E), α-SMA (F), and CD3 (G); and toluidine blue staining (arrowhead and arrows denote resting and activated mast cells, respectively) (H). Representative views are shown in the upper panels. Scale bars: 50 μm. Quantified data are shown in the lower panels (n = 5 each). *P < 0.05; **P < 0.01. Data are expressed as mean ± SEM.