Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo
Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo
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DOI：
10.1073/pnas.0610906104
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发表时间：
2007-08-28
影响因子：
11.1
通讯作者：
Molkentin, Jeffery D.
中科院分区：
文献类型：
--
作者：
Purcell, Nicole H.;Wilkins, Benjamin J.;Molkentin, Jeffery D.
MAPK信号通路是细胞分化、增殖、应激反应和细胞凋亡的重要调节因子。MAPK信号通路的一个分支最终导致ERK1/2激活，假设它调节心脏的生长和对生理和病理刺激的适应，因为它已知的激活反应几乎每一个应激和激动剂诱导的肥大刺激。在这里，我们研究了ERK1(-/-)和ERK(2+/-)小鼠，以及在心脏中可诱导表达ERK1/2失活磷酸酶的转基因小鼠中，ERK1/2信号在介导心脏肥大生长反应中的需求。尽管双特异性磷酸酶6在心脏中的诱导表达消除了基线和刺激后ERK1/2的磷酸化，但它不会减弱对压力超负荷刺激、神经内分泌激动剂注射或运动的肥大反应。同样，ERK1(-/-)和ERK(2+/-)小鼠在体内的病理或生理刺激诱导的心脏生长中没有减少。然而，阻断或删除心脏ERK1/2确实使心脏在长期压力超负荷后发生失代偿和衰竭，同时心肌细胞TUNEL增加。因此，ERK1/2信号不是在体内介导生理性或病理性心肌肥大所必需的，尽管它在对病理性刺激的反应中确实起到了保护作用。
MAPK signaling pathways function as critical regulators of cellular differentiation, proliferation, stress responsiveness, and apoptosis. One branch of the MAPK signaling pathway that culminates in ERK1/2 activation is hypothesized to regulate the growth and adaptation of the heart to both physiologic and pathologic stimuli, given its known activation in response to virtually every stress- and agonist-induced hypertrophic stimulus examined to date. Here we investigated the requirement of ERK1/2 signaling in mediating the cardiac hypertrophic growth response in Erk1(-/-) and Erk(2+/-) mice, as well as in transgenic mice with inducible expression of an ERK1/2-inactivating phosphatase in the heart, dual-specificity phosphatase 6. Although inducible expression of dual-specificity phosphatase 6 in the heart eliminated ERK1/2 phosphorylation at baseline and after stimulation without affecting any other MAPK, it did not diminish the hypertrophic response to pressure overload stimulation, neuroendocrine agonist infusion, or exercise. Similarly, Erk1(-/-) and Erk(2+/-) mice showed no reduction in pathologic or physiologic stimulus-induced cardiac growth in vivo. However, blockade or deletion of cardiac ERK1/2 did predispose the heart to decompensation and failure after long-term pressure overload in conjunction with an increase in myocyte TUNEL. Thus, ERK1/2 signaling is not required for mediating physiologic or pathologic cardiac hypertrophy in vivo, although it does play a protective role in response to pathologic stimuli.