Sphingosine-1-Phosphate-Specific G Protein-Coupled Receptors as Novel Therapeutic Targets for Atherosclerosis 英文参考文献.docVIP

Pharmaceuticals 2011, 4, 117-137; doi:10.3390/ph4010117 OPEN ACCESS pharmaceuticals ISSN 1424-8247 /journal/pharmaceuticals Review Sphingosine-1-Phosphate-Specific G Protein-Coupled Receptors as Novel Therapeutic Targets for Atherosclerosis Yasuo Okamoto *, Fei Wang, Kazuaki Yoshioka, Noriko Takuwa and Yoh Takuwa * Department of Physiology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8640, Japan; E-Mails: wf_0908@ (F.W.); yoshioka@med.kanazawa-u.ac.jp (K.Y.); ntakuwa@ishikawa-nu.ac.jp (N.T.) * Authors to whom correspondence should be addressed; E-Mails: linakura@med.kanazawa-u.ac.jp (Y.O.); ytakuwa@med.kanazawa-u.ac.jp (Y.T.); Tel.: +81-76-265-2165 and -2167; Fax: +81-76-234-4223. Received: 30 November 2010; in revised form: 25 December 2010 / Accepted: 4 January 2011 / Published: 4 January 2011 Abstract: Atherosclerosis is a chronic inflammatory process involving complex interactions of modified lipoproteins, monocyte-derived macrophages or foam cells, lymphocytes, endothelial cells (ECs), and vascular smooth muscle cells. Sphingosine-1-phosphate (S1P), a biologically active blood-borne lipid mediator, exerts pleiotropic effects such as cell proliferation, migration and cell-cell adhesion in a variety of cell types via five members of S1P-specific high-affinity G protein-coupled receptors (S1P1-S1P5). Among them, S1P1, S1P2 and S1P3 are major receptor subtypes which are widely expressed in various tissues. Available evidence suggest that S1P and HDL-bound S1P exert atheroprotective effects including inhibition of leukocyte adhesion and stimulation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) through the activation of Gi signaling pathway via S1P3 and probably S1P1, although there is still controversy. FTY720, the phosphorylation product of which is a high-affinity agonist for all S1P receptors excep