TRAIL death receptor 4 signaling via lysosome fusion and membrane raft clustering in coronary arterial endothelial cells: evidence from ASM knockout mice.
TRAIL death receptor 4 signaling via lysosome fusion and membrane raft clustering in coronary arterial endothelial cells: evidence from ASM knockout mice.
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DOI：
10.1007/s00109-012-0968-y
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发表时间：
2013-01
影响因子：
4.7
通讯作者：
Li, Pin-Lan
中科院分区：
文献类型：
--
作者：
Li, Xiang;Han, Wei-Qing;Boini, Krishna M.;Xia, Min;Zhang, Yang;Li, Pin-Lan
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）及其受体死亡受体4（DR 4）参与了内皮功能障碍和动脉粥样硬化的发展。然而，介导DR 4活化并导致内皮损伤的信号传导机制仍不清楚。我们最近发现，神经酰胺生产通过水解膜鞘磷脂的酸性鞘磷脂酶（ASM）的结果膜筏（MR）集群和形成重要的氧化还原信号平台，这在放大氧化还原信号在内皮细胞中发挥了至关重要的作用，导致内皮功能障碍。本研究旨在探讨TRAIL是否通过溶酶体融合和ASM激活触发MR聚集，从而传导跨膜氧化还原信号，改变内皮功能。使用共聚焦显微镜，我们发现TRAIL诱导MR聚类和其与DR 4在从野生型（Smpd 1 +/+）小鼠分离的冠状动脉内皮细胞（CAECs）中的共定位。此外，在Smpd 1 +/+ CAEC中，TRAIL触发ASM易位、神经酰胺产生和NADPH氧化酶聚集在MR簇中，而在Smpd 1 −/− CAEC中未发现这些观察结果。此外，ASM缺乏减少了CAEC中TRAIL诱导的O2−·产生，并消除了TRAIL诱导的小阻力动脉内皮依赖性血管舒张功能障碍。通过测量荧光共振能量转移（FRET），我们发现Lamp-1（溶酶体膜标记蛋白）和神经节苷脂GM 1（MR标记物）在Smpd 1 +/+ CAEC中一起运输，这在Smpd 1 −/− CAEC中不存在。同样，用特异性溶酶体探针对活细胞进行荧光成像表明，在Smpd 1 −/− CAEC中也不存在TRAIL诱导的溶酶体与膜融合。总之，这些结果表明，ASM是必需的TRAIL诱导的溶酶体运输和融合膜和MR氧化还原信号平台的形成，这可能在DR 4介导的CAEC氧化还原信号和随后的内皮功能障碍中发挥重要作用。
Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) and its receptor death receptor 4 (DR4) have been implicated in the development of endothelial dysfunction and atherosclerosis. However, the signaling mechanism mediating DR4 activation and leading to endothelial injury remains unclear. We recently demonstrated that ceramide production via hydrolysis of membrane sphingomyelin by acid sphingomyelinase (ASM) results in membrane raft (MRs) clustering and formation of important redox signaling platforms, which play a crucial role in amplifying redox signaling in endothelial cells leading to endothelial dysfunction. The present study aims to investigate whether TRAIL triggers MR clustering via lysosome fusion and ASM activation, thereby conducting transmembrane redox signaling and changing endothelial function. Using confocal microscopy, we found that TRAIL induced MR clustering and its co-localization with DR4 in coronary arterial endothelial cells (CAECs) isolated from wild-type (Smpd1+/+) mice. Further, TRAIL triggered ASM translocation, ceramide production and NADPH oxidase aggregation in MR clusters in Smpd1+/+ CAECs, whereas these observations were not found in Smpd1−/− CAECs. Moreover, ASM deficiency reduced TRAIL-induced O2−· production in CAECs and abolished TRAIL-induced impairment on endothelium-dependent vasodilation in small resistance arteries. By measuring fluorescence resonance energy transfer (FRET), we found that Lamp-1 (lysosome membrane marker protein) and ganglioside GM1 (MR marker) were trafficking together in Smpd1+/+ CAECs, which was absent in Smpd1−/− CAECs. Consistently, fluorescence imaging of living cells with specific lysosome probes demonstrated that TRAIL-induced lysosome fusion with membrane was also absent in Smpd1−/− CAECs. Taken together, these results suggest that ASM is essential for TRAIL-induced lysosomal trafficking and fusion with membrane and formation of MR redox signaling platforms, which may play an important role in DR4-mediated redox signaling in CAECs and consequent endothelial dysfunction.
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DOI：
10.1161/atvbaha.107.159772
发表时间：
2008-03-01
影响因子：
8.7
作者：
Jin, Si;Zhang, Yang;Li, Pin-Lan
通讯作者：
Li, Pin-Lan
影响因子：
3.5
作者：
Samhan-Arias, Alejandro K.;Angel Garcia-Bereguiain, Miguel;Gutierrez-Merino, Carlos
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Gutierrez-Merino, Carlos
DOI：
10.1152/ajpheart.00958.2009
发表时间：
2010-03-01
影响因子：
4.8
作者：
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通讯作者：
Li, Pin-Lan
影响因子：
4
作者：
Di Pietro, R;Mariggiò, MA;Pandolfi, A
通讯作者：
Pandolfi, A
影响因子：
3.4
作者：
Schramm, Michael;Herz, Jasmin;Utermoehlen, Olaf
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Utermoehlen, Olaf