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首页> 外文期刊>American Journal of Physiology >Activation of the neuregulin/ErbB system during physiological ventricular remodeling in pregnancy.
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Activation of the neuregulin/ErbB system during physiological ventricular remodeling in pregnancy.

机译：妊娠期生理性心室重构期间神经调节蛋白/ ErbB系统的激活。

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摘要

The neuregulin-1 (NRG1)/ErbB system has emerged as a paracrine endothelium-controlled system in the heart, which preserves left ventricular (LV) performance in pathophysiological conditions. Here, we analyze the activity and function of this system in pregnancy, which imparts a physiological condition of LV hemodynamic overload. NRG1 expression and ErbB receptor activation were studied by Western blot analyses in rats and mice at different stages of pregnancy. LV performance was evaluated by transthoracic echocardiography, and myocardial performance was assessed from twitches of isolated papillary muscles. NRG1/ErbB signaling was inhibited by oral treatment of animals with the dual ErbB1/ErbB2 tyrosine kinase inhibitor lapatinib. Analyses of LV tissue revealed that protein expression of different NRG1 isoforms and levels of phosphorylated ErbB2 and ErbB4 significantly increased after 1-2 wk of pregnancy. Lapatinib prevented phosphorylation of ErbB2 and ERK1/2, but not of ErbB4 and protein kinase B (Akt), revealing that lapatinib only partially inhibited NRG1/ErbB signaling in the LV. Lapatinib did not prevent pregnancy-induced changes in LV mass and did not cause apoptotic cell death or fibrosis in the LV. Nevertheless, lapatinib led to premature maternal death of approximately 25% during pregnancy and it accentuated pregnancy-induced LV dilatation, significantly reduced LV fractional shortening, and induced abnormalities of twitch relaxation (but not twitch amplitude) of isolated papillary muscles. This is the first study showing that the NRG1/ErbB system is activated, and plays a modulatory role, during physiological hemodynamic overload associated with pregnancy. Inhibiting this system during physiological overload may cause LV dysfunction in the absence of myocardial cell death.
机译：neuregulin-1（NRG1）/ ErbB系统已在心脏中作为旁分泌内皮控制系统出现，在病理生理条件下保留了左心室（LV）的功能。在这里，我们分析了该系统在怀孕期间的活动和功能，从而赋予了LV血液动力学超负荷的生理状况。通过蛋白质印迹分析在妊娠不同阶段的大鼠和小鼠中研究了NRG1表达和ErbB受体激活。通过经胸超声心动图评估左室功能，并从孤立的乳头肌抽搐评估心肌性能。通过双重ErbB1 / ErbB2酪氨酸激酶抑制剂拉帕替尼对动物进行口服治疗，可抑制NRG1 / ErbB信号传导。 LV组织的分析显示，怀孕1-2周后，不同NRG1亚型的蛋白表达以及磷酸化的ErbB2和ErbB4的水平显着增加。拉帕替尼可阻止ErbB2和ERK1 / 2的磷酸化，但不能阻止ErbB4和蛋白激酶B（Akt）的磷酸化，这表明拉帕替尼仅部分抑制LV中的NRG1 / ErbB信号传导。拉帕替尼不能预防妊娠引起的左室重量变化，也不会引起左室凋亡细胞死亡或纤维化。然而，拉帕替尼在怀孕期间导致约25％的产妇过早死亡，并加重了妊娠引起的左室扩张，明显降低了左室分数缩短，并导致了孤立的乳头肌抽搐松弛（但不是抽搐幅度）异常。这是第一项研究，表明NRG1 / ErbB系统在与怀孕有关的生理性血液动力学超负荷过程中被激活并起调节作用。在没有心肌细胞死亡的情况下，在生理超负荷期间抑制该系统可能会导致LV功能障碍。

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