Zhang Jianqing, Honbo Norman, Goetzl Edward J, Chatterjee Kanu, Karliner Joel S, Gray Mary O
Medical Service and Cardiology Section, Veterans Affairs Medical Center, San Francisco, CA, USA.
Am J Physiol Heart Circ Physiol. 2007 Nov;293(5):H3150-8. doi: 10.1152/ajpheart.00587.2006. Epub 2007 Aug 31.
Sphingosine 1-phosphate (S1P) is a biologically active lysophospholipid that serves as a key regulator of cellular differentiation and survival. Immune stimuli increase S1P synthesis and secretion by mast cells and platelets, implicating this molecule in tissue responses to injury and inflammation. Binding of S1P to G(i) protein-coupled receptors activates phosphatidylinositol 3-kinase and Akt in a variety of tissues. To elucidate the mechanisms by which S1P enhances adult cardiac myocyte survival during hypoxia, we used a mouse cell culture system in which S1P(1) receptors were observed to transduce signals from exogenous S1P, an S1P(1) receptor antibody with agonist properties, and the pharmacological agents FTY720 and SEW2871. S1P(1) receptor mRNA and protein were abundantly expressed by adult mouse cardiac myocytes. S1P-S1P(1) receptor axis enhancement of myocyte survival during hypoxia was abolished by phosphatidylinositol 3-kinase inhibition. S1P(1) receptor function was closely associated with activation of Akt, inactivation of GSK-3beta, and reduction of cytochrome c release from heart mitochondria. These observations highlight the importance of S1P(1) receptors on ventricular myocytes as mediators of inducible resistance against cellular injury during severe hypoxic stress.
鞘氨醇-1-磷酸（S1P）是一种具有生物活性的溶血磷脂，是细胞分化和存活的关键调节因子。免疫刺激会增加肥大细胞和血小板中S1P的合成与分泌，表明该分子参与组织对损伤和炎症的反应。S1P与G(i)蛋白偶联受体结合可激活多种组织中的磷脂酰肌醇3激酶和Akt。为了阐明S1P在缺氧期间增强成年心肌细胞存活的机制，我们使用了一种小鼠细胞培养系统，在该系统中观察到S1P(1)受体可转导来自外源性S1P、具有激动剂特性的S1P(1)受体抗体以及药物FTY720和SEW2871的信号。成年小鼠心肌细胞大量表达S1P(1)受体mRNA和蛋白。磷脂酰肌醇3激酶抑制可消除缺氧期间S1P-S1P(1)受体轴对心肌细胞存活的增强作用。S1P(1)受体功能与Akt的激活、GSK-3β的失活以及心脏线粒体细胞色素c释放的减少密切相关。这些观察结果突出了心室肌细胞上S1P(1)受体作为严重缺氧应激期间诱导细胞抗损伤的介质的重要性。
