The Sphingosine-1-phospate receptor 1 mediates S1P action during cardiac development.
The Sphingosine-1-phospate receptor 1 mediates S1P action during cardiac development.
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DOI：
10.1186/1471-213x-11-37
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发表时间：
2011-06-13
影响因子：
--
通讯作者：
Wendler CC
中科院分区：
文献类型：
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作者：
Poulsen RR;McClaskey CM;Rivkees SA;Wendler CC
鞘氨醇-1-磷酸(S1P)是一种具有生物活性的鞘磷脂代谢产物，可影响细胞的分化、增殖和迁移等活动。S1P通过五种不同的细胞表面受体S1P1-5R发挥作用，其中S1P1R在发育中的心脏中表达水平最高。S1P1R对血管成熟至关重要，它的缺失会导致胚胎在胚胎14.5岁时死亡；然而，它在心脏早期发育中的作用尚不清楚。我们先前的研究表明，S1P水平的改变对体外培养的房室管发育有不利影响，S1P水平降低导致细胞死亡，S1P水平升高抑制细胞迁移和内皮细胞向间充质细胞转化(EMT)。我们通过实时定量聚合酶链式反应分析确定，在发育中的心脏中，S1P1R的表达至少比其他S1P受体高10倍。免疫组织化学分析显示，S1P1R蛋白在发育中的房室内皮细胞和心肌细胞中均有表达。利用房室管培养物，我们观察到FTY720(S1P1，3，4，5R激动剂)或KRP203(S1P1R特异性激动剂)处理的房室管培养物与S1P处理的作用相似，包括诱导细胞圆化，抑制细胞迁移和抑制EMT。在体内，胚胎心脏的形态分析显示，S1P1R-/-心脏畸形，心肌组织减少。与S1P1R+/+相比，E12.5 S1P1R-/-心脏除了心肌组织减少外，还破坏了心壁和小梁的形态，外层致密层增厚和排列紊乱，纤维连接蛋白(FN)沉积减少。心肌的减少伴随着细胞增殖的减少，而不是细胞凋亡的增加。这些数据表明，S1P1R是房室管培养中S1P作用的主要介体，体内S1P1R表达的缺失会导致胚胎心脏畸形，部分原因是纤维连接蛋白表达减少，细胞增殖减少。
Sphingosine-1-phosophate (S1P) is a biologically active sphingolipid metabolite that influences cellular events including differentiation, proliferation, and migration. S1P acts through five distinct cell surface receptors designated S1P1-5R, with S1P1R having the highest expression level in the developing heart. S1P1R is critical for vascular maturation, with its loss leading to embryonic death by E14.5; however, its function during early cardiac development is not well known. Our previous studies demonstrated that altered S1P levels adversely affects atrioventricular (AV) canal development in vitro, with reduced levels leading to cell death and elevated levels inhibiting cell migration and endothelial to mesenchymal cell transformation (EMT). We determined, by real-time PCR analysis, that S1P1R was expressed at least 10-fold higher than other S1P receptors in the developing heart. Immunohistochemical analysis revealed S1P1R protein expression in both endothelial and myocardial cells in the developing atrium and ventricle. Using AV canal cultures, we observed that treatment with either FTY720 (an S1P1,3,4,5R agonist) or KRP203 (an S1P1R-specific agonist) caused similar effects on AV canal cultures as S1P treatment, including induction of cell rounding, inhibition of cell migration, and inhibition of EMT. In vivo, morphological analysis of embryonic hearts at E10.5 revealed that S1P1R-/- hearts were malformed with reduced myocardial tissue. In addition to reduced myocardial tissue, E12.5 S1P1R-/- hearts had disrupted morphology of the heart wall and trabeculae, with thickened and disorganized outer compact layer and reduced fibronectin (FN) deposition compared to S1P1R+/+ littermates. The reduced myocardium was accompanied by a decrease in cell proliferation but not an increase in apoptosis. These data indicate that S1P1R is the primary mediator of S1P action in AV canal cultures and that loss of S1P1R expression in vivo leads to malformed embryonic hearts, in part due to reduced fibronectin expression and reduced cell proliferation.