PDK1在小鼠心血管发育过程中的作用和机制研究
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摘要
PI3k/PDK1/Akt (phosphoinositide-3 kinase/phosphoinositide-dependent kinase 1/protein kinase B瞵酸肌醇3激酶/磷脂酰肌醇依赖性激酶1/蛋白激酶B)信号通路在心血管系统中的作用研究最早是由Walsh和他的团队开始的,他们发现Akt可以促进心肌细胞在体外培养系统中存活。随后一些研究发现,在心肌细胞中过表达Akt可以导致心脏肥厚和心力衰竭。紧接着Akt在胚胎发育过程中的作用开始受到关注。近期报道,Akt1/3双敲除的小鼠表现出心脏发育异常,这与先前Dario Alessi研究发现和PDK1敲除小鼠表现为严重心脏病表型相一致。PDK1与VEGFR(vascular endothelial growth factor receptor血管内皮生长因子受体)和Tie2受体一样是酪氨酸激酶受体(receptor tyrosine kinases,RTKs)的一个重要的下游信号分子,在发育和肿瘤发生过程中扮演了重要的角色。在过去的二十年,PI3k/PDK1信号通路在心肌肥厚和心脏保护方面的功能研究比较详细,但是PDK1在心血管发育过程中的作用仍没有阐明。本实验目的即研究PDK1在心血管发育过程中的作用及其机制。
为此我们在小鼠的内皮细胞中特异性的敲除了PDK1,这些小鼠在胚胎期表现为多部位的出血和心包积液,大约在胚胎期11.5天死亡。组织学分析解释存在血管重构和发育的缺陷，在心脏中心内膜和肌小梁/心肌结构紊乱，由于内皮向间充质细胞转化(epithelial/endothelial-mesenchymal transdifferentiation,EMT)过程的缺陷和肉皮细胞凋亡的增加导致不能形成心内膜垫和瓣膜。体外培养房室管(atrioventricular canal,AVC)显示爬出的间充质细胞明显减少。在内皮细胞中Snail蛋白明显减少,并且在核外聚集.在体外培养的AVC细胞中加入SnailS6A突变的病毒,能够有效地挽救EMT的缺陷。另外在体外培养过程加入过表达Akt的腺病毒同样能挽救EMT的缺陷。同时敲除PDK1和PTEN(phosphatase and tensin homolog deleted on chromosome ten,人第10号染色体缺失的磷酸酶及张力蛋白同源的基因)可以使内皮细胞内单独敲除PDK1的小鼠死亡时间延后一天,并且心内膜垫的发育趋正常。
综上所述,这些结果表明PDK1在心血管发育过程中通过Akt和Snail扮演了重要的角色。本研究在不久的将来可能可以为临床治疗提供理论支持,可以通过调节Akt信号通路治疗心血管疾病。
The role of PI3k/PDK1/Akt pathway in cardiac system was first revealed by the pioneering study performed by Walsh and colleagues which documented Akt's function to promote cardiomyocyte survival in vivo. Shortly after. several groups reported almost simultaneously. cardiac hypertrophy and failure in transgenic mice with Akt overexpression in cardiomyocytes. Afterwards. PI3k/PDK1/Akt pathway's involvement in embryonic development has been unveiled along with the generation and characterization of Akt individual knockout mice and subsequent compound Akt deletion mice. We first reported a heart developmental defect in Akt1/3 double knockout mice, which is in consistency with the earlier work performed in Dario Alessi's group showing severe cardiac phenotype in PDK (phosphoinositide-dependent kinase 1) germ-line deletion mice. One essential downstream signaling pathway of receptor tyrosine kinases (RTKs). such as vascular endothelial growth factor receptor (VEGFR) and the Tie2 receptor. is the phosphoinositide-3 kinase (PI3K)-phosphoinositide-dependent protein kinase 1 (PDK1)-Akt/protein kinase B (PKB) cascade that plays a criticalrole in development and tumorigenesis. In the past decade. the function of PI3k/PDKl pathway in heart hypertrophy and cardiac protection has been extensively investigated while PDK1's role in heart development is much less studied. The aim of present study was to show the role and mechanism of PDK 1 in cardiovascular development.
Here, we deleted PDK1 specifically in endothelial cells in mice. These mice displayed hemorrhage and hydropericardium and died at approximately embryonic day 11.5 (El1.5). Histological analysis revealed defective vascular remodeling and development and disrupted integrity between the endothelium and trabeculae/ myocardium in the heart. The atrioventricular canal (AVC) cushion and valves failed to form, indicating a defect in epithelial-mesenchymal transition (EMT). together with increased endothelial apoptosis. Consistently, ex vivo AVC explant culture showed impeded mesenchymal outgrowth. Snail protein was reduced and was absent from the nucleus in AVC cells. Delivery of the Snail S6A mutant to the AVC explant effectively rescued EMT defects. Furthermore. adenoviral Akt delivery rescued EMT defects in AVC explant culture, and deletion of PTEN delayed embryonic lethality of PDK1 endothelial deletion mice by 1 day and rendered normal development of the AVC cushion in the PDK1-deficient heart.
Taken together. these results have revealed an essential role of PDK1 in cardiovascular development through activation of Akt and Snail. The data presented here could be promising for therapeutic applications. In the future. it will be helpful to modulate Akt signaling to improve cardiovascular complications in human patients.
为此我们在小鼠的内皮细胞中特异性的敲除了PDK1,这些小鼠在胚胎期表现为多部位的出血和心包积液,大约在胚胎期11.5天死亡。组织学分析解释存在血管重构和发育的缺陷，在心脏中心内膜和肌小梁/心肌结构紊乱，由于内皮向间充质细胞转化(epithelial/endothelial-mesenchymal transdifferentiation,EMT)过程的缺陷和肉皮细胞凋亡的增加导致不能形成心内膜垫和瓣膜。体外培养房室管(atrioventricular canal,AVC)显示爬出的间充质细胞明显减少。在内皮细胞中Snail蛋白明显减少,并且在核外聚集.在体外培养的AVC细胞中加入SnailS6A突变的病毒,能够有效地挽救EMT的缺陷。另外在体外培养过程加入过表达Akt的腺病毒同样能挽救EMT的缺陷。同时敲除PDK1和PTEN(phosphatase and tensin homolog deleted on chromosome ten,人第10号染色体缺失的磷酸酶及张力蛋白同源的基因)可以使内皮细胞内单独敲除PDK1的小鼠死亡时间延后一天,并且心内膜垫的发育趋正常。
综上所述,这些结果表明PDK1在心血管发育过程中通过Akt和Snail扮演了重要的角色。本研究在不久的将来可能可以为临床治疗提供理论支持,可以通过调节Akt信号通路治疗心血管疾病。
The role of PI3k/PDK1/Akt pathway in cardiac system was first revealed by the pioneering study performed by Walsh and colleagues which documented Akt's function to promote cardiomyocyte survival in vivo. Shortly after. several groups reported almost simultaneously. cardiac hypertrophy and failure in transgenic mice with Akt overexpression in cardiomyocytes. Afterwards. PI3k/PDK1/Akt pathway's involvement in embryonic development has been unveiled along with the generation and characterization of Akt individual knockout mice and subsequent compound Akt deletion mice. We first reported a heart developmental defect in Akt1/3 double knockout mice, which is in consistency with the earlier work performed in Dario Alessi's group showing severe cardiac phenotype in PDK (phosphoinositide-dependent kinase 1) germ-line deletion mice. One essential downstream signaling pathway of receptor tyrosine kinases (RTKs). such as vascular endothelial growth factor receptor (VEGFR) and the Tie2 receptor. is the phosphoinositide-3 kinase (PI3K)-phosphoinositide-dependent protein kinase 1 (PDK1)-Akt/protein kinase B (PKB) cascade that plays a criticalrole in development and tumorigenesis. In the past decade. the function of PI3k/PDKl pathway in heart hypertrophy and cardiac protection has been extensively investigated while PDK1's role in heart development is much less studied. The aim of present study was to show the role and mechanism of PDK 1 in cardiovascular development.
Here, we deleted PDK1 specifically in endothelial cells in mice. These mice displayed hemorrhage and hydropericardium and died at approximately embryonic day 11.5 (El1.5). Histological analysis revealed defective vascular remodeling and development and disrupted integrity between the endothelium and trabeculae/ myocardium in the heart. The atrioventricular canal (AVC) cushion and valves failed to form, indicating a defect in epithelial-mesenchymal transition (EMT). together with increased endothelial apoptosis. Consistently, ex vivo AVC explant culture showed impeded mesenchymal outgrowth. Snail protein was reduced and was absent from the nucleus in AVC cells. Delivery of the Snail S6A mutant to the AVC explant effectively rescued EMT defects. Furthermore. adenoviral Akt delivery rescued EMT defects in AVC explant culture, and deletion of PTEN delayed embryonic lethality of PDK1 endothelial deletion mice by 1 day and rendered normal development of the AVC cushion in the PDK1-deficient heart.
Taken together. these results have revealed an essential role of PDK1 in cardiovascular development through activation of Akt and Snail. The data presented here could be promising for therapeutic applications. In the future. it will be helpful to modulate Akt signaling to improve cardiovascular complications in human patients.
引文
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