Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart
Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart
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DOI：
10.1074/jbc.m200347200
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发表时间：
2002-06-21
影响因子：
4.8
通讯作者：
Rosenzweig, A
中科院分区：
文献类型：
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作者：
Matsui, T;Li, L;Rosenzweig, A
丝氨酸-苏氨酸激酶Akt在体内外均能抑制心肌细胞凋亡。然而，心脏中慢性Akt激活的影响尚不清楚。为了解决这个问题，我们产生了转基因小鼠（TG+）的心脏特异性表达的组成型活性突变体的Akt（myr-Akt）驱动的肌球蛋白重链-α启动子。三个TG+创始人（9-19周）突然死亡，心脏大面积扩张。两个可行的TG+线（TG 564和TG 20）来自独立的创始人证明心脏特异性转基因表达以及Akt和p70 S6激酶的激活。TG 564（n = 19）显示心脏肥大，心脏/体重比是同窝出生的小鼠的2.3倍（n = 17，p < 0.005）。TG 20（n = 18）具有较不显著的心脏肥大，心脏/体重比比同窝出生的小鼠大1.6倍（a = 17，p < 0.005）。分离的TG 564肌细胞也是肥大的，表面积比同窝出生的大1.7倍（p < 0.000001）。两条线的超声心动图显示向心性肥大和保留的收缩功能。缺血再灌注后，TG+组梗死面积比TG-组减少50%（17 +/- 3%比34 +/-4%，p < 0.001）。因此，慢性Akt激活足以引起一系列表型，从具有保留的收缩功能和心脏保护的中度心脏肥大到大量心脏扩张和猝死。
The serine-threonine kinase, Akt, inhibits cardiomyocyte apoptosis acutely both in vitro and in vivo. However, the effects of chronic Akt activation in the heart are unknown. To address this issue, we generated transgenic mice (TG+) with cardiac-specific expression of a constitutively active mutant of Akt (myr-Akt) driven by the myosin heavy chain-alpha promoter. Three TG+ founders (9-19 weeks) died suddenly with massive cardiac dilatation. Two viable TG+ lines (TG564 and TG20) derived from independent founders demonstrated cardiac-specific transgene expression as well as activation of Akt and p70S6 kinase. TG564 (n = 19) showed cardiac hypertrophy with a heart/body weight ratio 2.3-fold greater than littermates (n = 17, p < 0.005). TG20 (n = 18) had less marked cardiac hypertrophy with a heart/body weight ratio 1.6-fold greater than littermates (a = 17, p < 0.005). Isolated TG564 myocytes were also hypertrophic with surface areas 1.7-fold greater than littermates (p < 0.000001). Echocardiograms in both lines demonstrated concentric hypertrophy and preserved systolic function. After ischemia-reperfusion, TG+ had a 50% reduction in infarct size versus TG- (17 +/- 3% versus 34 +/- 4%, p < 0.001). Thus, chronic Akt activation is sufficient to cause a spectrum of phenotypes from moderate cardiac hypertrophy with preserved systolic function and cardioprotection to massive cardiac dilatation and sudden death.