Constitutively active MEK1 rescues cardiac dysfunction caused by overexpressed GSK-3α during aging and hemodynamic pressure overload
Constitutively active MEK1 rescues cardiac dysfunction caused by overexpressed GSK-3α during aging and hemodynamic pressure overload
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DOI：
10.1152/ajpheart.00415.2012
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发表时间：
2012-10-01
影响因子：
4.8
通讯作者：
Zhai, Peiyong
中科院分区：
文献类型：
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作者：
Maejima, Yasuhiro;Galeotti, Jonathan;Zhai, Peiyong
Maejima Y，Galeotti J，Molkentin JD，Sadoshima J，Zhai P.组成性活性MEK 1挽救衰老和血液动力学压力过载期间过度表达GSK-3 α引起的心功能障碍。Am J Physiol Heart Circ Physiol 303：H979-H988，2012年。首次发表于2012年8月17日; doi：10.1152/ajpheart.00415.2012.- GSK-3 α的表达在老化心脏和血流动力学超负荷心脏中增加。过表达GSK-3 α抑制ERK并增强压力超负荷（PO）诱导的心功能不全。我们研究了MEK 1/ERK通路的抑制是否有助于过表达GSK-3 α诱导的心脏反应，使用组成型活性MEK 1（CA-MEK 1）/GSK-3 α双基因小鼠（双基因小鼠），这是通过交叉心脏特异性GSK-3 α转基因小鼠（Tg-GSK）和心脏特异性CA-MEK 1转基因小鼠（Tg-MEK 1）获得的。在Tg-GSK中观察到的ERK磷酸化抑制在双基因小鼠中消除。在12个月，左心室（LV）的重量/胫骨长度，左心室重量/体重，心肌细胞的大小显着小于Tg-GSK比非转基因小鼠（NTg），但Tg-MEK 1和双基因小鼠之间没有显着差异。Tg-GSK组的左室射血分数（LVEF）、短轴缩短率（FS）和压力随时间的变化显著低于NTg组，但在双基因小鼠和Tg-MEK 1之间无显著差异。Tg-GSK细胞凋亡的增加在双基因小鼠中被消除，尽管纤维化的增加没有。PO后，Tg-GSK中观察到的心脏肥大的减少和细胞凋亡的增强在双基因小鼠中被废除。灌胃后，Tg-GSK组的LVEF和FS较假手术组显著降低，而NTg、Tg-MEK 1和双基因小鼠的LVEF和FS较假手术组无显著降低。Tg-MEK 1与双基因小鼠PO后的LVEF和FS无显著性差异。总之，抑制MEK 1/ERK通路介导了心肌细胞中GSK-3 α过表达引起的肥大抑制和心功能障碍。
Maejima Y, Galeotti J, Molkentin JD, Sadoshima J, Zhai P. Constitutively active MEK1 rescues cardiac dysfunction caused by overexpressed GSK-3 alpha during aging and hemodynamic pressure overload. Am J Physiol Heart Circ Physiol 303: H979-H988, 2012. First published August 17, 2012; doi:10.1152/ajpheart.00415.2012.-Expression of GSK-3 alpha is increased in aging hearts and those subjected to hemodynamic overload. Overexpressed GSK-3 alpha inhibits ERK and enhances pressure overload (PO)-induced cardiac dysfunction. We studied whether suppression of the MEK1/ERK pathway contributes to cardiac responses induced by overexpressed GSK-3 alpha using constitutively active MEK1 (CA-MEK1)/GSK-3 alpha bigenic mice (bigenic mice), which were obtained by crossing cardiac-specific GSK-3 alpha transgenic mice (Tg-GSK) and cardiac-specific CA-MEK1 transgenic mice (Tg-MEK1). The suppression of ERK phosphorylation observed in Tg-GSK was eliminated in bigenic mice. At 12 mo, left ventricular (LV) weight/tibia length, LV weight/body weight, and cardiac myocyte size were significantly smaller in Tg-GSK than in nontransgenic mice (NTg), but were not significantly different between Tg-MEK1 and bigenic mice. The LV ejection fraction (LVEF), fractional shortening (FS), and change in pressure over time were significantly lower in Tg-GSK than in NTg, but were not significantly different between bigenic mice and Tg-MEK1. The increase in apoptosis in Tg-GSK was abolished in bigenic mice, although the increase in fibrosis was not. After PO, the decrease in cardiac hypertrophy and the enhancement of apoptosis seen in Tg-GSK were abrogated in bigenic mice. After PO, the LVEF and FS were significantly reduced in Tg-GSK compared with its sham, but not in NTg, Tg-MEK1, or bigenic mice compared with their respective shams. There was no significant difference in LVEF and FS between bigenic mice and Tg-MEK1 after PO. In conclusion, inhibition of the MEK1/ERK pathway mediates the hypertrophy suppression and cardiac dysfunction caused by GSK-3 alpha overexpression in cardiac myocytes.