Lack of ataxia telangiectasia mutated kinase induces structural and functional changes in the heart: role in β-adrenergic receptor-stimulated apoptosis.
Lack of ataxia telangiectasia mutated kinase induces structural and functional changes in the heart: role in β-adrenergic receptor-stimulated apoptosis.
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DOI：
10.1113/expphysiol.2011.061812
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发表时间：
2012-04
影响因子：
2.7
通讯作者：
Singh K
中科院分区：
文献类型：
--
作者：
Foster CR;Zha Q;Daniel LL;Singh M;Singh K
共济失调毛细血管扩张突变激酶(ATM)参与细胞周期检查点、DNA修复和细胞凋亡。β肾上腺素能受体(β-AR)刺激可诱导心肌细胞凋亡。在这里，我们分析了atm基因敲除(KO)小鼠的基本心肌结构和功能，并验证了atm调节β-AR刺激的心肌细胞凋亡的假说。以野生型(WT)和KO小鼠为模型，观察加或不加L-异丙肾上腺素治疗24小时后左心结构和功能、心肌细胞凋亡、纤维化及纤维化、肥大和细胞凋亡相关蛋白表达的变化。KO小鼠的体重和心脏重量较轻。M型超声心动图显示KO小鼠的室间隔厚度和左心室内径减少。多谱勒超声心动图显示KO小鼠早期峰值速度(E波)与晚期(A波)充盈速度之比增大。KO心脏的基础纤维化和心肌细胞横截面积较大。纤维化相关基因(CTGF、PAI-1、MMP-2)和肥大相关基因(ANP)在KO心脏中的表达较高。β-AR刺激增加两组心肌细胞凋亡的程度相似。β-AR刺激后JNKs的激活、P53的表达和磷酸化仅见于WT组。KO-Sham组AKT磷酸化水平较低，刺激β-AR后，KO组AKT磷酸化水平持续降低。刺激β-AR对两组大鼠GSK-3β的激活程度相似。因此，缺乏ATM会导致心脏结构和功能的改变，导致心肌纤维化和心肌细胞肥大。β-AR诱导的WT心肌细胞凋亡与P53和JNKS依赖机制有关，而AKT活性降低可能是导致心肌细胞凋亡增加的原因之一。
Ataxia telangiectasia mutated kinase (ATM) is involved in cell cycle checkpoints, DNA repair and apoptosis. β-adrenergic receptor (β-AR) stimulation induces cardiac myocyte apoptosis. Here we analyzed basal myocardial structure and function in ATM knockout (KO) mice, and tested the hypothesis that ATM modulates β-AR-stimulated myocyte apoptosis. Left ventricular (LV) structure and function, myocyte apoptosis, fibrosis and expression of fibrosis-, hypertrophy- and apoptosis-related proteins were examined in wild-type (WT) and KO mice with or without L-isoproterenol treatment for 24h. Body and heart weights were lower in KO mice. M-mode echocardiography showed reduced septal wall thicknesses and LV diameters in KO mice. Doppler echocardiography showed increased ratio of early peak velocity (E wave) to that of the late (A wave) LV filling in KO mice. Basal fibrosis and myocyte cross-sectional area was greater in KO hearts. Expression of fibrosis-related genes (CTGF, PAI-1 and MMP-2) and hypertrophy-related gene (ANP) was higher in KO hearts. β-AR stimulation increased myocyte apoptosis to a similar extent in both groups. Activation of JNKs, and expression and phosphorylation of p53 in response to β-AR stimulation was only observed in WT group. Akt phosphorylation was lower in KO-sham and remained lower following β-AR stimulation in KO group. β-AR stimulation activated GSK-3β to a similar extent in both groups. Thus, lack of ATM induces structural and functional changes in the heart with enhanced myocardial fibrosis and myocyte hypertrophy. β-AR-stimulated apoptosis in WT hearts is associated with p53- and JNKs-dependent mechanism, while decreased Akt activity may play a role in increased myocyte apoptosis in the absence of ATM.
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影响因子：
7.7
作者：
Huynh K;McMullen JR;Julius TL;Tan JW;Love JE;Cemerlang N;Kiriazis H;Du XJ;Ritchie RH
通讯作者：
Ritchie RH
DOI：
10.1152/ajpheart.00207.2003
发表时间：
2003-09-01
影响因子：
4.8
作者：
Hayashidani, S;Tsutsui, H;Takeshita, A
通讯作者：
Takeshita, A
影响因子：
3.5
作者：
Mujumdar, VS;Smiley, LM;Tyagi, SC
通讯作者：
Tyagi, SC
影响因子：
3
作者：
Miyamoto, Shigeki;Murphy, Anne N.;Brown, Joan Heller
通讯作者：
Brown, Joan Heller
影响因子：
64.5
作者：
Barlow, C;Hirotsune, S;WynshawBoris, A
通讯作者：
WynshawBoris, A