Activation or inactivation of cardiac Akt/mTOR signaling diverges physiological from pathological hypertrophy
Activation or inactivation of cardiac Akt/mTOR signaling diverges physiological from pathological hypertrophy
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DOI：
10.1002/jcp.21197
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发表时间：
2008-02-01
影响因子：
5.6
通讯作者：
Ellingsen, Oyvind
中科院分区：
文献类型：
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作者：
Kemi, Ole Johan;Ceci, Marcello;Ellingsen, Oyvind
心肌细胞肥大根据施加在心肌上的应力而不同。虽然压力超负荷诱导的心肌细胞肥大与收缩功能低下有关，但运动训练后的生理性肥大与收缩力的保持或增加有关。我们确定了运动诱导的生理性和压力超负荷诱导的病理性肥大中心肌Akt信号转导与下游底物和胎儿基因再激活的激活状态。C57 BL/6 J小鼠在最大摄氧量（VO 2 max）的85-90%下进行6周5天/周的跑步机训练，或进行1周或8周的横向主动脉缩窄（TAC）。用SDS-PAGE测定总蛋白和磷酸化蛋白水平，用实时RT-PCR测定胎儿基因。在运动训练后的生理性肥大心脏中，总Akt蛋白水平不变，但Akt在丝氨酸473处慢性过度磷酸化。这伴随着哺乳动物雷帕霉素靶蛋白（mTOR）的激活，测量为其两种底物的磷酸化：核糖体蛋白S6激酶-I（S6 KI）和真核翻译起始因子-4E结合蛋白-I（4 E-BPI）。运动训练没有重新激活胎儿基因程序（β-肌球蛋白重链，心房利钠因子，骨骼肌肌动蛋白）。相比之下，TAC后的压力过载在1周后已经重新激活了胎儿基因，并且在8周后部分灭活了Akt/mTOR通路和下游底物。总之，心肌Akt/mTOR信号通路的相反方向的变化似乎可以区分生理性和病理性肥大;运动训练与Akt/mTOR通路的激活和失活相关。
Cardiomyocyte hypertrophy differs according to the stress exerted on the myocardium. While pressure overload-induced cardiomyocyte hypertrophy is associated with depressed contractile function, physiological hypertrophy after exercise training associates with preserved or increased inotropy. We determined the activation state of myocardial Akt signaling with downstream substrates and fetal gene reactivation in exercise-induced physiological and pressure overload-induced pathological hypertrophies. C57BL/6J mice were either treadmill trained for 6 weeks, 5 days/week, at 85-90% of maximal oxygen uptake (VO2max), or underwent transverse aortic constriction (TAC) for 1 or 8 weeks. Total and phosphorylated protein levels were determined with SDS-PAGE, and fetal genes by real-time RT-PCR. In the physiologically hypertrophied heart after exercise training, total Akt protein level was unchanged, but Akt was chronically hyperphosphorylated at serine 473. This was accompanied by activation of the mammalian target of rapamycin (mTOR), measured as phosphorylation of its two substrates: the ribosomal protein S6 kinase-I (S6KI) and the eukaryotic translation initiation factor-4E binding protein-I (4E-BPI). Exercise training did not reactivate the fetal gene program (beta-myosin heavy chain, atrial natriuretic factor, skeletal muscle actin). In contrast, pressure overload after TAC reactivated fetal genes already after I week, and partially inactivated the Akt/mTOR pathway and downstream substrates after 8 weeks. In conclusion, changes in opposite directions of the myocardial Akt/mTOR signal pathway appears to distinguish between physiological and pathological hypertrophies; exercise training associating with activation and pressure overload associating with inactivation of the Akt/mTOR pathway.