The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice
The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice
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DOI：
10.1093/emboj/19.23.6341
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发表时间：
2000-12-01
期刊：
影响因子：
11.4
通讯作者：
Molkentin, JD
中科院分区：
文献类型：
--
作者：
Bueno, OF;De Windt, LJ;Molkentin, JD
丝裂原活化蛋白激酶（MAPK）级联的成员，例如细胞外信号调节激酶（ERK）、c-Jun N-末端激酶（JNK）和p38被认为是培养中心肌细胞肥大生长的重要调节剂。然而，单个MAPK通路在体内发挥的作用尚未得到广泛评价。在这里，我们产生了9个转基因小鼠品系与心脏限制性表达的激活MEK 1 cDNA的心脏。MEK 1转基因小鼠表现出向心性肥大，没有心肌病或致死性的迹象，长达12个月的年龄。MEK 1转基因小鼠显示出心脏功能的显著增加，如通过超声心动图和分离的工作心脏制备所测量的，没有随时间推移失代偿的迹象。MEK 1转基因小鼠和MEK 1腺病毒感染的新生心肌细胞均表现出ERK 1/2激活，而不是p38或JNK激活，MEK 1转基因小鼠和MEK 1腺病毒感染的培养心肌细胞也部分抵抗凋亡刺激。本研究的结果表明，MEK 1-ERK 1/2信号通路刺激与增强的心脏功能和部分抵抗心肌肥厚相关的生理性肥大反应。
Members of the mitogen-activated protein kinase (MAPK) cascade such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 are implicated as important regulators of cardiomyocyte hypertrophic growth in culture. However, the role that individual MAPK pathways play in vivo has not been extensively evaluated. Here we generated nine transgenic mouse lines with cardiac-restricted expression of an activated MEK1 cDNA in the heart. MEK1 transgenic mice demonstrated concentric hypertrophy without signs of cardiomyopathy or lethality up to 12 months of age. MEK1 transgenic mice showed a dramatic increase in cardiac function, as measured by echocardiography and isolated working heart preparation, without signs of decompensation over time. MEK1 transgenic mice and MEK1 adenovirus-infected neonatal cardiomyocytes each demonstrated ERK1/2, but not p38 or JNK, activation, MEK1 transgenic mice and MEK1 adenovirus-infected cultured cardiomyocytes were also partially resistant to apoptotic stimuli. The results of the present study indicate that the MEK1-ERK1/2 signaling pathway stimulates a physiologic hypertrophy response associated with augmented cardiac function and partial resistance to apoptotsis.