Endothelial Gab1 Deletion Accelerates Angiotensin II-Dependent Vascular Inflammation and Atherosclerosis in Apolipoprotein E Knockout Mice
Endothelial Gab1 Deletion Accelerates Angiotensin II-Dependent Vascular Inflammation and Atherosclerosis in Apolipoprotein E Knockout Mice
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DOI：
10.1253/circj.cj-11-1507
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发表时间：
2012-08-01
影响因子：
3.3
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Higuchi, Kaori;Nakaoka, Yoshikazu;Komuro, Issei
背景资料：对接蛋白Grb 2相关结合物1（Gab 1）在各种生长因子、细胞因子和许多其它分子的信号转导中具有关键作用。我们以前的报告表明，Gab 1是必不可少的出生后血管生成通过分析内皮特异性Gab 1基因敲除（Gab 1 ECKO）小鼠。然而，Gab 1在动脉粥样硬化中的作用仍然未知。本研究的目的是阐明内皮细胞Gab 1在血管炎症和atherosclerosis.Methods和Results中的作用：我们intercrossed Gab 1 ECKO小鼠与载脂蛋白E（ApoE）基因敲除（ApoEKO）小鼠。6个月大的雄性ApoEKO/Gab 1 ECKO和同窝对照（ApoEKO）小鼠通过渗透输注微型泵用血管紧张素II（AngII）处理。AngII治疗后，ApoEKO/Gab 1 ECKO小鼠与对照小鼠相比，动脉粥样硬化和动脉瘤形成显著增强。与对照小鼠相比，ApoEKO/Gab 1 ECKO小鼠主动脉中促炎细胞因子的产生显著增强。此外，Kruppel样因子（KLF）2（KLF 2）和KLF 4，内皮稳态的关键转录因子的表达水平显着降低，在ApoEKO/Gab 1 ECKO小鼠的主动脉内皮与对照小鼠相比。一致，血管细胞粘附分子-1的表达和巨噬细胞浸润的主动脉壁增强ApoEKO/Gab 1 ECKO小鼠与control mice.Conclusions：总的来说，内皮细胞Gab 1缺失加速AngII依赖性血管炎症和动脉粥样硬化ApoE空背景推测与下调KLF 2和KLF 4。(Circ J 2012; 76：2031-2040）
Background: Docking protein Grb2-associated binder 1 (Gab1) has critical roles in signal transduction of various growth factors, cytokines, and numerous other molecules. Our previous reports show that Gab1 is essential for postnatal angiogenesis through the analysis of endothelium-specific Gab1 knockout (Gab1ECKO) mice. However, the role of Gab1 in atherosclerosis remains unknown. The aim of the present study was to elucidate the role of endothelial Gab1 in vascular inflammation and atherosclerosis.Methods and Results: We intercrossed Gab1ECKO mice with apolipoprotein E (ApoE) knockout (ApoEKO) mice. Six-month-old male ApoEKO/Gab1ECKO and littermate control (ApoEKO) mice were treated with angiotensin II (AngII) via an osmotic infusion mini-pump. After AngII treatment, ApoEKO/Gab1ECKO mice showed significantly enhanced atherosclerosis and aneurysm formation compared with control mice. The production of proinflammatory cytokines in the aorta was significantly enhanced in ApoEKO/Gab1ECKO mice compared with control mice. Furthermore, the expression levels of Kruppel-like factor (KLF) 2 (KLF2) and KLF4, key transcription factors for endothelial homeostasis, were significantly reduced in the aortic endothelium of ApoEKO/Gab1ECKO mice compared with those of control mice. Consistently, both vascular cell adhesion molecule-1 expression and macrophage infiltration on the aortic walls were enhanced in ApoEKO/Gab1ECKO mice compared with control mice.Conclusions: Collectively, endothelial Gab1 deletion accelerates AngII-dependent vascular inflammation and atherosclerosis on ApoE-null background presumably in association with downregulation of KLF2 and KLF4. (Circ J 2012; 76: 2031-2040)