Decreased vascular lesion formation in mice with inducible endothelial-specific expression of protein kinase Akt
Decreased vascular lesion formation in mice with inducible endothelial-specific expression of protein kinase Akt
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DOI：
10.1172/jci26223
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发表时间：
2006-02-01
影响因子：
15.9
通讯作者：
Liao, JK
中科院分区：
文献类型：
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作者：
Mukai, Y;Rikitake, Y;Liao, JK
为了确定内皮Akt是否可以影响血管病变形成，产生了具有组成型活性Akt转基因的突变小鼠，其可以使用tet-off系统诱导靶向血管内皮（EC-Akt Tg小鼠）。多西环素停药后，EC-Akt Tg小鼠表现出内皮特异性Akt活性和NO产生增加。在颈动脉结扎引起血流停止后，与未诱导的EC-Akt Tg小鼠和对照同窝小鼠相比，诱导的EC-Akt Tg小鼠的新生内膜形成减弱。为了确定eNOS在介导这些作用中的作用，用N-ω-硝基-L-精氨酸甲酯（L-NAME）处理小鼠。在用L-NAME处理的诱导EC-Akt Tg小鼠中，新生内膜形成在较小程度上减弱，这表明一些血管保护作用是NO独立的。事实上，Akt的内皮激活导致结扎动脉中EC凋亡较少。免疫染色显示血管损伤后诱导的EC-Akt Tg小鼠的炎症和增殖变化减少。这些发现表明Akt的内皮激活通过增加NO产生、保护功能性内皮层以及抑制血管壁中的炎症和增殖变化来抑制损伤形成。这些结果表明，单独增强内皮Akt活性可能在血管损伤后具有治疗益处。
To determine whether endothelial Akt could affect vascular lesion formation, mutant mice with a constitutively active Akt transgene, which could be inducibly targeted to the vascular endothelium using the tet-off system (EC-Akt Tg mice), were generated. After withdrawal of doxycycline, EC-Akt Tg mice demonstrated increased endothelial-specific Akt activity and NO production. After blood flow cessation caused by carotid artery ligation, neointimal formation was attenuated in induced EC-Akt Tg mice compared with noninduced EC-Akt Tg mice and control littermates. To determine the role of eNOS in mediating these effects, mice were treated with N-omega-nitro-L-arginine methyl ester (L-NAME). Neointimal formation was attenuated to a lesser extent in induced EC-Akt Tg mice treated with L-NAME, suggesting that some of the vascular protective effects were NO independent. Indeed, endothelial activation of Akt resulted in less EC apoptosis in ligated arteries. Immunostaining demonstrated decreased inflammatory and proliferative changes in induced EC-Akt Tg mice after vascular injury. These findings indicate that endothelial activation of Akt suppresses lesion formation via increased NO production, preservation of functional endothelial layer, and suppression of inflammatory and proliferative changes in the vascular wall. These results suggest that enhancing endothelial Akt activity alone could have therapeutic benefits after vascular injury.