Akt1及其异构体在心脏发育过程中的作用研究
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摘要
Akt/蛋白激酶B (PKB)是AGC kinase家族(包括PKA, PKG以及PKC)中的一个亚家族。在哺乳动物中,Akt/PKB家族包含三个成员(isoform)分别称为Akt1/PKBa, Akt2/PKBβ和Akt3/PKByo它们被处于不同染色体上的不同的基因编码。尽管3个异构体蛋白间有很高的同源性和类似的结构域,但是通过遗传学研究发现他们的在发育和生理学功能上的作用并不一致。通过联合敲除Akt1和Akt2、Akt1和Akt3、或者Akt2和Akt3的研究,发现3个基因在发育和生理学功能上的作用有叠加效应。P13K-PDK1-Akt (P13K, phosphoinositide-3 kinase; PDK1, phosphoinositide-dependent protein kinase)信号通路在多种生物学过程中发挥着非常重要的作用,包括细胞生存、增殖、代谢和器官发育过程。
以前的研究发现全身性Akt1敲除的小鼠出生后表现出较高的死亡率,但是死亡的原因一直没有被阐明。本论文中的研究结果发现了出生后1天的Akt1敲除小鼠表现出明显的心脏发育缺陷的表型,主要包括心脏房间隔缺损(Atrial Spetal Defect, ASD)、室间隔缺损(Ventricular Spetal Defect, VSD)和心室肌厚度变薄。运用心脏B超进行心脏功能学研究,发现Akt1敲除小鼠在出生后2天,表现出明显的心脏功能下降。这些结果表明Akt1敲除小鼠出生后高死亡率可能是由于心脏的表型引起的。进一步研究发现Akt1敲除的小鼠心肌细胞增殖明显降低,心脏室间隔中的毛细血管密度明显减少。
机制研究表明,Akt1敲除的小鼠从胚胎期12.5天到出生1天的心脏均表现出p38活性的升高,和以前的报道p38的活性和心脏的增殖成负相关的结果相一致。通过遗传学的手段,把Akt1敲除小鼠和p38a敲除小鼠交配,发现p38a缺失一半后可以挽救Akt1敲除小鼠出生后死亡率高、心脏发育缺陷和心肌细胞增殖减少的表型。
由于Akt1和p38α的缺失都可能造成胎盘的发育缺陷,而胎盘发育缺陷也是导致心脏发育缺陷和功能改变的因素之一,所以为了排除胎盘的影响,我们制作了Akt1心脏特异性敲除的小鼠(使用Mesp1-cre小鼠,心脏祖细胞中特异性表达Cre重组酶)。蛋白水平分析表明敲除的效率并不完全。组织学分析结果表明,部分Akt1心脏特异性敲除的小鼠也表现出了心脏发育缺陷。这些结果显示心脏中残留的少量Akt可能也能够部分维持心脏的发育和功能。
以前的研究表明3个Akt异构体之间有功能叠加的效应,所以我们分析了Akt1F/F:Mesp1-cre+/-;Akt3-/-小鼠,发现了这种基因型的小鼠大约死于胚胎期第14.5天(E14.5),所有死亡的小鼠均表现出明显的心脏发育缺陷和较薄的心肌壁。
综合以上我们的研究结果表明,Akt1及其异构体Akt3在维持正常心脏发育和功能上发挥着重要的作用,并且这种作用是有基因剂量依赖性的。
Mammals have three Akt/PKB (protein kinase B) isoforms, termed Akt1/PKBa, Akt2/PKBβ, and Akt3/PKBy (hereafter collectively referred to as Akt), that are encoded by three distinct genes localized on different chromosomes. Although the three Akt proteins share high homology and display similar domain structures, mouse genetic studies have demonstrated that they play overlapping but distinct roles in development and physiology. The P13K-PDK1-PKB/Akt (P13K, phosphoinositide-3 kinase; PDK1, phosphoinositide-dependent protein kinase) signaling pathway plays critical roles in a variety of biological processes, including cell survival, growth and proliferation, metabolism and organogenesis.
Akt1-deficient mice have a high rate of neonatal mortality with an unknown cause. Here, we report that histological analysis revealed that Akt1-deficient embryos and newborns have heart defects and a decreased rate of cell proliferation. In addition, echocardiography demonstrated that the heart function of these mice is decreased. Further investigation revealed that the Akt1 deficiency caused substantial activation of p38MAPK in the heart. Breeding the Akt1-deficient mice to mice that are heterozygous for a null p38a gene partially rescued the heart defects, significantly decreased post-natal mortality, and restored normal patterns of cardiomyocytes proliferation.
Because both the intrauterine environment and the fetal-maternal interface are critical for fetal development and growth, the placental defects need to be separated from those observed in the heart in this study. This separation was accomplished using a cardiac-specific knockout for Akt1. Unexpectedly, the/Mesp1-Cre-mediated, cardiac-specific Akt1 knockout mice appeared normal. Further analysis showed that Akt1 was present at very low levels in the Akt1F/F;Mesp1-Cre+/- mice hearts. This low level was enough to maintain a partial role in the functioning of the heart.
Previous study indicated that other Akt isoforms exhibit gene dosage effects relative to Akt1, and we determined that Akt1F/F;Mesp1-Cre+/-;Akt3homo mice had an embryonic lethal phenotype. Further analysis showed that the Akt1F/F;Mesp1-Cre+/-;Akt3homo mice die at about embryonic day 14.5 (E14.5). By E14.5, all Akt1F/F;Mesp1-Cre+/-;Akt3homo mice at E14.5 have congenital heart defects and a thinner myocardium. Cardiac cell proliferation was significantly decreased, which may contribute to the congenital heart defects and thinner myocardium.
In conclusion, these results suggest that Akt isoforms play an important role in heart development, potentially in a dosage-dependent manner. Thus, the roles of the Akt isoforms need to be further studied.
以前的研究发现全身性Akt1敲除的小鼠出生后表现出较高的死亡率,但是死亡的原因一直没有被阐明。本论文中的研究结果发现了出生后1天的Akt1敲除小鼠表现出明显的心脏发育缺陷的表型,主要包括心脏房间隔缺损(Atrial Spetal Defect, ASD)、室间隔缺损(Ventricular Spetal Defect, VSD)和心室肌厚度变薄。运用心脏B超进行心脏功能学研究,发现Akt1敲除小鼠在出生后2天,表现出明显的心脏功能下降。这些结果表明Akt1敲除小鼠出生后高死亡率可能是由于心脏的表型引起的。进一步研究发现Akt1敲除的小鼠心肌细胞增殖明显降低,心脏室间隔中的毛细血管密度明显减少。
机制研究表明,Akt1敲除的小鼠从胚胎期12.5天到出生1天的心脏均表现出p38活性的升高,和以前的报道p38的活性和心脏的增殖成负相关的结果相一致。通过遗传学的手段,把Akt1敲除小鼠和p38a敲除小鼠交配,发现p38a缺失一半后可以挽救Akt1敲除小鼠出生后死亡率高、心脏发育缺陷和心肌细胞增殖减少的表型。
由于Akt1和p38α的缺失都可能造成胎盘的发育缺陷,而胎盘发育缺陷也是导致心脏发育缺陷和功能改变的因素之一,所以为了排除胎盘的影响,我们制作了Akt1心脏特异性敲除的小鼠(使用Mesp1-cre小鼠,心脏祖细胞中特异性表达Cre重组酶)。蛋白水平分析表明敲除的效率并不完全。组织学分析结果表明,部分Akt1心脏特异性敲除的小鼠也表现出了心脏发育缺陷。这些结果显示心脏中残留的少量Akt可能也能够部分维持心脏的发育和功能。
以前的研究表明3个Akt异构体之间有功能叠加的效应,所以我们分析了Akt1F/F:Mesp1-cre+/-;Akt3-/-小鼠,发现了这种基因型的小鼠大约死于胚胎期第14.5天(E14.5),所有死亡的小鼠均表现出明显的心脏发育缺陷和较薄的心肌壁。
综合以上我们的研究结果表明,Akt1及其异构体Akt3在维持正常心脏发育和功能上发挥着重要的作用,并且这种作用是有基因剂量依赖性的。
Mammals have three Akt/PKB (protein kinase B) isoforms, termed Akt1/PKBa, Akt2/PKBβ, and Akt3/PKBy (hereafter collectively referred to as Akt), that are encoded by three distinct genes localized on different chromosomes. Although the three Akt proteins share high homology and display similar domain structures, mouse genetic studies have demonstrated that they play overlapping but distinct roles in development and physiology. The P13K-PDK1-PKB/Akt (P13K, phosphoinositide-3 kinase; PDK1, phosphoinositide-dependent protein kinase) signaling pathway plays critical roles in a variety of biological processes, including cell survival, growth and proliferation, metabolism and organogenesis.
Akt1-deficient mice have a high rate of neonatal mortality with an unknown cause. Here, we report that histological analysis revealed that Akt1-deficient embryos and newborns have heart defects and a decreased rate of cell proliferation. In addition, echocardiography demonstrated that the heart function of these mice is decreased. Further investigation revealed that the Akt1 deficiency caused substantial activation of p38MAPK in the heart. Breeding the Akt1-deficient mice to mice that are heterozygous for a null p38a gene partially rescued the heart defects, significantly decreased post-natal mortality, and restored normal patterns of cardiomyocytes proliferation.
Because both the intrauterine environment and the fetal-maternal interface are critical for fetal development and growth, the placental defects need to be separated from those observed in the heart in this study. This separation was accomplished using a cardiac-specific knockout for Akt1. Unexpectedly, the/Mesp1-Cre-mediated, cardiac-specific Akt1 knockout mice appeared normal. Further analysis showed that Akt1 was present at very low levels in the Akt1F/F;Mesp1-Cre+/- mice hearts. This low level was enough to maintain a partial role in the functioning of the heart.
Previous study indicated that other Akt isoforms exhibit gene dosage effects relative to Akt1, and we determined that Akt1F/F;Mesp1-Cre+/-;Akt3homo mice had an embryonic lethal phenotype. Further analysis showed that the Akt1F/F;Mesp1-Cre+/-;Akt3homo mice die at about embryonic day 14.5 (E14.5). By E14.5, all Akt1F/F;Mesp1-Cre+/-;Akt3homo mice at E14.5 have congenital heart defects and a thinner myocardium. Cardiac cell proliferation was significantly decreased, which may contribute to the congenital heart defects and thinner myocardium.
In conclusion, these results suggest that Akt isoforms play an important role in heart development, potentially in a dosage-dependent manner. Thus, the roles of the Akt isoforms need to be further studied.
引文
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