Akt and MAPK signaling mediate pregnancy-induced cardiac adaptation
Akt and MAPK signaling mediate pregnancy-induced cardiac adaptation
复制标题
DOI：
10.1152/japplphysiol.00027.2012
复制
发表时间：
2012-05-01
影响因子：
3.3
通讯作者：
Leinwand, Leslie A.
中科院分区：
文献类型：
--
作者：
Chung, Eunhee;Yeung, Fan;Leinwand, Leslie A.
Chung E，Yeung F，Leinwand LA. Akt和MAPK信号转导介导妊娠诱导的心脏适应。J Appl Physiol 112：1564-1575，2012.首次发表于2012年2月16日; doi：10.1152/japplphysiol.00027.2012.-虽然运动诱导的心脏适应的信号通路已被广泛研究，但对导致心脏对妊娠反应的分子机制知之甚少。本研究的目的是定义定义怀孕小鼠心脏的形态，功能和基因表达模式，并确定介导这种反应的信号通路。将小鼠分为三组：非妊娠间情对照组、妊娠中期组和妊娠晚期组。妊娠的两个时间点均与显著的心脏肥大相关。Akt和ERK 1/2的促生存信号级联在妊娠小鼠的心脏中被激活，而应激激酶p38被降低。考虑到Akt在妊娠中的活化及其在心脏肥大中的已知作用，在表达Akt的心脏特异性活化（肉豆蔻酰化）形式（myrAkt）或其下游靶点糖原合成酶激酶3 β（caGSK 3 β）的心脏特异性组成性活性（抗病理性肥大）形式的小鼠中测试了对妊娠的肥大反应。这些小鼠的妊娠诱导的心脏肥大反应显着减弱。最后，我们测试了妊娠相关性激素是否可以诱导肥大和改变分离的新生大鼠心室肌细胞（NRVMs）的信号通路。事实上，孕酮，而不是雌二醇治疗增加NRVM细胞大小通过磷酸化ERK 1/2。抑制MEK 1有效地阻断了孕酮诱导的细胞肥大。综上所述，我们的研究表明，妊娠诱导的心脏肥大是由Akt和ERK 1/2途径的激活介导的。
Chung E, Yeung F, Leinwand LA. Akt and MAPK signaling mediate pregnancy-induced cardiac adaptation. J Appl Physiol 112: 1564-1575, 2012. First published February 16, 2012; doi:10.1152/japplphysiol.00027.2012.-Although the signaling pathways underlying exercise-induced cardiac adaptation have been extensively studied, little is known about the molecular mechanisms that result in the response of the heart to pregnancy. The objective of this study was to define the morphological, functional, and gene expression patterns that define the hearts of pregnant mice, and to identify the signaling pathways that mediate this response. Mice were divided into three groups: nonpregnant diestrus control, midpregnancy, and late pregnancy. Both time points of pregnancy were associated with significant cardiac hypertrophy. The prosurvival signaling cascades of Akt and ERK1/2 were activated in the hearts of pregnant mice, while the stress kinase, p38, was decreased. Given the activation of Akt in pregnancy and its known role in cardiac hypertrophy, the hypertrophic response to pregnancy was tested in mice expressing a cardiac-specific activated (myristoylated) form of Akt (myrAkt) or a cardiac-specific constitutively active (antipathologic hypertrophic) form of its downstream target, glycogen synthase kinase 3 beta (caGSK3 beta). The pregnancy-induced hypertrophic responses of hearts from these mice were significantly attenuated. Finally, we tested whether pregnancy-associated sex hormones could induce hypertrophy and alter signaling pathways in isolated neonatal rat ventricular myocytes (NRVMs). In fact, progesterone, but not estradiol treatment increased NRVM cell size via phosphorylation of ERK1/2. Inhibition of MEK1 effectively blocked progesterone-induced cellular hypertrophy. Taken together, our study demonstrates that pregnancy-induced cardiac hypertrophy is mediated by activation of Akt and ERK1/2 pathways.