Akt3 overexpression in the heart results in progression from adaptive to maladaptive hypertrophy.
Akt3 overexpression in the heart results in progression from adaptive to maladaptive hypertrophy.
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DOI：
10.1016/j.yjmcc.2004.12.002
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发表时间：
2005-02-01
影响因子：
5
通讯作者：
Shiojima, Ichiro
中科院分区：
文献类型：
--
作者：
Taniyama, Yoshiaki;Ito, Masahiro;Shiojima, Ichiro
AKT是一种丝氨酸/苏氨酸激酶，介导细胞对外界刺激的各种反应。在哺乳动物Akt的三个成员(Akt1、Akt2和AKT3)中，AKT3是独一无二的，因为它有一个选择性剪接变异体，缺少羧基末端调节磷酸化位点。然而，对AKT3及其剪接变异体在体内的功能知之甚少。在这项研究中，我们研究了AKT3剪接变异体通过在心脏中过度表达其激活形式的潜在功能。心脏特异的AKT3转基因(TG)小鼠表现出明显的心肌肥大。TG心脏的收缩功能在4周龄和12周龄时保持不变，但在20周龄时受损。当使用心脏毒性药物阿霉素(Dox)治疗时，4周龄的TG小鼠的存活率提高，收缩功能得到保护。然而，在12周龄注射Dox时，这些心脏保护作用并不明显，而在20周龄注射Dox时，TG小鼠的死亡率甚至高于野生型动物。AKT3TG心脏内源性Akt1和Akt2蛋白及磷酸化水平下调，提示Akt信号在Akt蛋白含量水平存在负反馈调节。综上所述，AKT3剪接变异体在体内具有功能，促进心脏生长并介导心脏保护作用。然而，AKT3的持续过表达会导致收缩功能障碍，增加心脏损伤的易感性。因此，Akt信号的持续激活导致从适应性肥厚进展到非适应性肥厚。
Akt is a serine/threonine kinase that mediates a variety of cellular responses to external stimuli. Among the three members of mammalian Akt (Akt1, Akt2 and Akt3), Akt3 is unique in that it has an alternatively spliced variant that lacks the carboxy-terminal regulatory phosphorylation site. However, little is known regarding in vivo functions of Akt3 and its spliced variant. In this study we investigated the potential functions of the Akt3 spliced variant by overexpressing its activated form in the heart. Cardiac-specific Akt3 transgenic (TG) mice exhibited marked cardiac hypertrophy. Contractile function of TG hearts was preserved at 4 and 12 weeks, but was impaired at 20 weeks of age. When treated with cardiotoxic drug doxorubicin (Dox), TG mice at 4 weeks of age exhibited improved survival and preserved contractile function. However, these cardioprotective effects were not evident when Dox was injected at 12 weeks of age, and TG mice exhibited even higher mortality rate than wild-type animals when Dox was injected at 20 weeks of age. Endogenous Akt1 and Akt2 protein and phosphorylation levels were downregulated in Akt3 TG hearts, suggesting the existence of negative feedback regulation of Akt signaling at the level of Akt protein amount. Taken together, the Akt3 spliced variant is functional in vivo, promotes cardiac growth and mediates cardioprotective effects. However, continuous overexpression of Akt3 results in contractile dysfunction and increased susceptibility to cardiac injury. Thus, sustained activation of Akt signaling results in progression from adaptive to maladaptive hypertrophy.