Endothelial Gab1 deficiency aggravates splenomegaly in portal hypertension independent of angiogenesis.
Endothelial Gab1 deficiency aggravates splenomegaly in portal hypertension independent of angiogenesis.
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内皮 Gab1 缺陷会加重门静脉高压症的脾肿大，与血管生成无关。
DOI：
10.1152/ajpgi.00292.2014
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发表时间：
2015-03
期刊：
影响因子：
--
通讯作者：
Luo, Jincai
中科院分区：
文献类型：
--
作者：
Huo, Yingqing;Li, Wei;Shibuya, Masabumi;Luo, Jincai
某些病理改变，包括血管生成，积极地促进了门脉高压症(PH)脾肿大的发病机制，尽管具体的分子和细胞机制仍不清楚。在这项研究中，我们证明了内皮GRB-2相关结合蛋白1(GAB1)在PH相关性脾肿大中发挥了不依赖于血管生成的负面作用。门静脉部分结扎诱导的pH显著增强内皮细胞GAB1的表达，且呈时间依赖关系。与对照组相比，内皮特异性GAB1基因敲除(EGKO)小鼠的脾大小显著增加，而PH水平保持不变。病理分析表明，EGKO小鼠在扩大的脾组织中出现了更严重的白髓过度活跃和纤维化，但在脾和肠系膜组织中血管生成较少。机制研究表明，EGKO小鼠内皮型一氧化氮合酶(ENOS)的磷酸化水平明显低于对照组。此外，还观察到肝纤维化和炎症相关转录因子[如Krüppel-like factor2和KLF5]的异常调节以及细胞因子基因(如肿瘤坏死因子-α和IL-6)的上调。因此，我们认为内皮细胞GAB1通过预防内皮功能障碍和促炎/促纤维化细胞因子的过度产生，在抑制PH脾肿大的发病机制中发挥多途径的作用。
Certain pathological changes, including angiogenesis, actively contribute to the pathogenesis of splenomegaly in portal hypertension (PH), although the detailed molecular and cellular mechanisms remain elusive. In this study, we demonstrated that endothelial Grb-2-associated binder 1 (Gab1) plays a negative role in PH-associated splenomegaly independent of angiogenesis. PH, which was induced by partial portal vein ligation, significantly enhanced Gab1 expression in endothelial cells in a time-dependent manner. Compared with controls, endothelium-specific Gab1 knockout (EGKO) mice exhibited a significant increase in spleen size while their PH levels remained similar. Pathological analysis indicated that EGKO mice developed more severe hyperactive white pulp and fibrosis in the enlarged spleen but less angiogenesis in both the spleen and mesenteric tissues. Mechanistic studies showed that the phosphorylation of endothelial nitric oxide synthase (eNOS) in EGKO mice was significantly lower than in controls. In addition, the dysregulation of fibrosis and inflammation-related transcription factors [e.g., Krüppel-like factor (KLF) 2 and KLF5] and the upregulation of cytokine genes (e.g., TNF-α and IL-6) were observed in EGKO mice. We thus propose that endothelial Gab1 mediates multiple pathways in inhibition of the pathogenesis of splenomegaly in PH via prevention of endothelial dysfunction and overproduction of proinflammatory/profibrotic cytokines.
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影响因子：
82.9
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影响因子：
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作者：
Johannes V. van Thienen;J. Fledderus;R. Dekker;J. Rohlena;Gerben A van Ijzendoorn;N. Kootstra;H. Pannekoek;A. Horrevoets
通讯作者：
Johannes V. van Thienen;J. Fledderus;R. Dekker;J. Rohlena;Gerben A van Ijzendoorn;N. Kootstra;H. Pannekoek;A. Horrevoets
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作者：
Berzigotti, Annalisa;Zappoli, Paola;Zoli, Marco
通讯作者：
Zoli, Marco
影响因子：
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作者：
R. Gusberg;S. Peterec;B. Sumpio;G. Meier
通讯作者：
R. Gusberg;S. Peterec;B. Sumpio;G. Meier
DOI：
10.1007/978-3-642-37078-6_144
发表时间：
2015-01-23
期刊：
PanVascular Medicine
影响因子：
--
作者：
Morales-Ruiz M;Rodríguez-Vita J;Ribera J;Jiménez W
通讯作者：
Jiménez W