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論文 |
論文
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Wang, Fei ; Okamoto, Yasuo ; Inoki, Isao ; Yoshioka, Kazuaki ; Du, Wa ; Qi, Xun ; Takuwa, Noriko ; Gonda, Koichi ; Yamamoto, Yasuhiko ; Ohkawa, Ryunosuke ; Nishiuchi, Takumi ; Sugimoto, Naotoshi ; Yatomi, Yutaka ; Mitsumori, Kunitoshi ; Asano, Masahide ; Kinoshita, Makoto ; Takuwa, Yoh
概要:
金沢大学医薬保健研究域医学系<br />Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that has pleiotropic effects in
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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.
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| 2.
論文 |
論文
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Yoshioka, Kazuaki ; Yoshida, Kotaro ; Cui, Hong ; Wakayama, Tomohiko ; Takuwa, Noriko ; Okamoto, Yasuo ; Du, Wa ; Qi, Xun ; Asanuma, Ken ; Sugihara, Kazushi ; Aki, Sho ; Miyazawa, Hidekazu ; Biswas, Kuntal ; Nagakura, Chisa ; Ueno, Masaya ; Iseki, Shoichi ; Schwartz, Robert J. ; Okamoto, Hiroshi ; Sasaki, Takehiko ; Matsui, Osamu ; Asano, Masahide ; Adams, Ralf H. ; Takakura, Nobuyuki ; Takuwa, Yoh
概要:
The class II α-isoform of phosphatidylinositol 3-kinase (PI3K-C2α) is localized in endosomes, the trans-Golgi network an
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d clathrin-coated vesicles; however, its functional role is not well understood. Global or endothelial-cell-specific deficiency of PI3K-C2α resulted in embryonic lethality caused by defects in sprouting angiogenesis and vascular maturation. PI3K-C2α knockdown in endothelial cells resulted in a decrease in the number of PI3-phosphate-enriched endosomes, impaired endosomal trafficking, defective delivery of VE-cadherin to endothelial cell junctions and defective junction assembly. PI3K-C2α knockdown also impaired endothelial cell signaling, including vascular endothelial growth factor receptor internalization and endosomal RhoA activation. Together, the effects of PI3K-C2α knockdown led to defective endothelial cell migration, proliferation, tube formation and barrier integrity. Endothelial PI3K-C2α deficiency in vivo suppressed postischemic and tumor angiogenesis and diminished vascular barrier function with a greatly augmented susceptibility to anaphylaxis and a higher incidence of dissecting aortic aneurysm formation in response to angiotensin II infusion. Thus, PI3K-C2α has a crucial role in vascular formation and barrier integrity and represents a new therapeutic target for vascular disease.<br />In Press / 2013-03-18公開予定.
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