Synergy between sphingosine 1-phosphate and lipopolysaccharide signaling promotes an inflammatory, angiogenic and osteogenic response in human aortic valve interstitial cells.
Synergy between sphingosine 1-phosphate and lipopolysaccharide signaling promotes an inflammatory, angiogenic and osteogenic response in human aortic valve interstitial cells.
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1-磷酸鞘氨醇和脂多糖信号传导之间的协同作用可促进人主动脉瓣间质细胞的炎症、血管生成和成骨反应。
DOI：
10.1371/journal.pone.0109081
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
García-Rodríguez C
中科院分区：
文献类型：
--
作者：
Fernández-Pisonero I;López J;Onecha E;Dueñas AI;Maeso P;Crespo MS;San Román JA;García-Rodríguez C
鉴于生物活性脂质1-磷酸鞘氨醇参与心血管病理生理学，并且由于脂质蓄积和炎症是钙化性主动脉瓣狭窄的标志，因此研究了1-磷酸鞘氨醇对来自主动脉瓣和肺动脉瓣的人间质细胞中促炎/促成骨途径的作用。实时荧光定量PCR显示主动脉瓣间质细胞表达1-磷酸鞘氨醇受体。细胞暴露于1-磷酸鞘氨醇诱导促炎反应，其特征在于白细胞介素-6，白细胞介素-8和环氧合酶-2上调，如通过ELISA和Western印迹所观察到的。引人注目的是，用1-磷酸鞘氨醇加脂多糖处理细胞导致环氧合酶-2和细胞间粘附分子1的协同诱导，以及前列腺素E2（细胞间粘附分子1的可溶形式）和促血管生成因子血管内皮生长因子-A的分泌。值得注意的是，与对照瓣膜相比，狭窄的主动脉瓣间质细胞中的协同效应显著更高，而肺动脉瓣细胞中的协同效应显著更低，肺动脉瓣很少发生狭窄。siRNA和药理学分析揭示了1-磷酸鞘氨醇受体1/3和Toll样受体4的参与，以及通过p38/MAPK、蛋白激酶C和NF-κB的下游信号传导。至于促成骨途径，1-磷酸鞘氨醇诱导钙沉积和钙化标志物骨形态发生蛋白-2和碱性磷酸酶的表达，并增强脂多糖的作用，这种作用通过抑制1-磷酸鞘氨醇受体3/2信号传导而部分阻断。总之，1-磷酸鞘氨醇受体和Toll样受体4信号传导之间的相互作用导致主动脉瓣间质细胞中炎症、血管生成和成骨途径的协同上调，这似乎与主动脉瓣狭窄的发病机制相关，并可能允许新的治疗方法的开始。
Given that the bioactive lipid sphingosine 1-phosphate is involved in cardiovascular pathophysiology, and since lipid accumulation and inflammation are hallmarks of calcific aortic stenosis, the role of sphingosine 1-phosphate on the pro-inflammatory/pro-osteogenic pathways in human interstitial cells from aortic and pulmonary valves was investigated. Real-time PCR showed sphingosine 1-phosphate receptor expression in aortic valve interstitial cells. Exposure of cells to sphingosine 1-phosphate induced pro-inflammatory responses characterized by interleukin-6, interleukin-8, and cyclooxygenase-2 up-regulations, as observed by ELISA and Western blot. Strikingly, cell treatment with sphingosine 1-phosphate plus lipopolysaccharide resulted in the synergistic induction of cyclooxygenase-2, and intercellular adhesion molecule 1, as well as the secretion of prostaglandin E2, the soluble form of the intercellular adhesion molecule 1, and the pro-angiogenic factor vascular endothelial growth factor-A. Remarkably, the synergistic effect was significantly higher in aortic valve interstitial cells from stenotic than control valves, and was drastically lower in cells from pulmonary valves, which rarely undergo stenosis. siRNA and pharmacological analysis revealed the involvement of sphingosine 1-phosphate receptors 1/3 and Toll-like receptor-4, and downstream signaling through p38/MAPK, protein kinase C, and NF-κB. As regards pro-osteogenic pathways, sphingosine 1-phosphate induced calcium deposition and the expression of the calcification markers bone morphogenetic protein-2 and alkaline phosphatase, and enhanced the effect of lipopolysaccharide, an effect that was partially blocked by inhibition of sphingosine 1-phosphate receptors 3/2 signaling. In conclusion, the interplay between sphingosine 1-phosphate receptors and Toll-like receptor 4 signaling leads to a cooperative up-regulation of inflammatory, angiogenic, and osteogenic pathways in aortic valve interstitial cells that seems relevant to the pathogenesis of aortic stenosis and may allow the inception of new therapeutic approaches.
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通讯作者：
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影响因子：
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