Sphingosine-1-phosphate signaling and biological activities in the cardiovascular system.
Sphingosine-1-phosphate signaling and biological activities in the cardiovascular system.
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DOI：
10.1016/j.bbalip.2008.04.003
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发表时间：
2008-09
期刊：
影响因子：
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通讯作者：
Y. Takuwa;Y. Okamoto;K. Yoshioka;N. Takuwa
中科院分区：
文献类型：
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作者：
Y. Takuwa;Y. Okamoto;K. Yoshioka;N. Takuwa
血浆溶血磷脂介质鞘氨醇-1-磷酸（S1 P）在体内仅由鞘氨醇激酶（SPHK）1和SPHK 2产生，并且主要通过G蛋白偶联的S1 P受体的三个成员S1 P1、S1 P2和S1 P3起作用而发挥多种生物学和病理生理学作用。内皮细胞上表达的S1 P1通过激活eNOS、抑制血管通透性和诱导内皮细胞趋化性介导胚胎血管成熟和维持血管完整性。相比之下，S1 P2在血管平滑肌细胞（VSMC）和某些类型的肿瘤细胞上以高水平表达，通过G12/13和Rho依赖性机制抑制Rac和细胞迁移。在大鼠新生内膜VSMCs中，S1 P1上调介导局部产生血小板衍生生长因子，这是血管重塑的关键因素。内皮细胞表达的S1 P3还可介导对S1 P的趋化作用，并在一定的血管床中通过产生NO来舒张血管，对血管的完整性起保护作用。S1 P3在VSMCs和心脏窦房结细胞上的表达分别介导血管升压和负性变时作用。此外，S1 P3与S1 P2、SPHK 1共同对急性心肌缺血具有保护作用。然而，我们最近的工作表明，SPHK 1过表达参与体内心肌细胞变性和纤维化，部分通过S1 P激活S1 P3信号。我们还表明，外源性管理S1 P加速缺血肢体的新血管形成和血流恢复，这表明其对血管生成治疗的有用性。这些结果为S1 P受体亚型特异性药物干预作为心血管疾病和癌症的新治疗方法提供了证据。
The plasma lysophospholipid mediator sphingosine-1-phosphate (S1P) is produced exclusively by sphingosine kinase (SPHK) 1 and SPHK2 in vivo, and plays diverse biological and pathophysiological roles by acting largely through three members of the G protein-coupled S1P receptors, S1P1, S1P2and S1P3. S1P1expressed on endothelial cells mediates embryonic vascular maturation and maintains vascular integrity by contributing to eNOS activation, inhibiting vascular permeability and inducing endothelial cell chemotaxis via Gi-coupled mechanisms. By contrast, S1P2, is expressed in high levels on vascular smooth muscle cells (VSMCs) and certain types of tumor cells, inhibiting Rac and cell migration via a G12/13-and Rho-dependent mechanism. In rat neointimal VSMCs, S1P1is upregulated to mediate local production of platelet-derived growth factor, which is a key player in vascular remodeling. S1P3expressed on endothelial cells also mediates chemotaxis toward S1P and vasorelaxation via NO production in certain vascular bed, playing protective roles for vascular integrity. S1P3expressed on VSMCs and cardiac sinoatrial node cells mediates vasopressor and negative chronotropic effect, respectively. In addition, S1P3, together with S1P2and SPHK1, is suggested to play a protective role against acute myocardial ischemia. However, our recent work indicates that overexpressed SPHK1 is involved in cardiomyocyte degeneration and fibrosis in vivo, in part through S1P activation of the S1P3signaling. We also demonstrated that exogenously administered S1P accelerates neovascularization and blood flow recovery in ischemic limbs, suggesting its usefulness for angiogenic therapy. These results provide evidence for S1P receptor subtype-specific pharmacological intervention as a novel therapeutic approach to cardiovascular diseases and cancer.