Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.
King's College London British Heart Foundation Centre of Excellence, School of Cardiovascular Medicine & Sciences, London, UK.
ESC Heart Fail. 2019 Oct;6(5):1015-1026. doi: 10.1002/ehf2.12497. Epub 2019 Jul 19.
Volume overload (VO) and pressure overload (PO) induce differential cardiac remodelling responses including distinct signalling pathways. Extracellular signal-regulated kinases 1 and 2 (ERK1/2), key signalling components in the mitogen-activated protein kinase (MAPK) pathways, modulate cardiac remodelling during pressure overload (PO). This study aimed to assess their role in VO-induced cardiac remodelling as this was unknown.
Aortocaval fistula (Shunt) surgery was performed in mice to induce cardiac VO. Two weeks of Shunt caused a significant reduction of cardiac ERK1/2 activation in wild type (WT) mice as indicated by decreased phosphorylation of the TEY (Thr-Glu-Tyr) motif (-28% as compared with Sham controls, P < 0.05). Phosphorylation of other MAPKs was unaffected. For further assessment, transgenic mice with cardiomyocyte-specific ERK2 overexpression (ERK2tg) were studied. At baseline, cardiac ERK1/2 phosphorylation in ERK2tg mice remained unchanged compared with WT littermates, and no overt cardiac phenotype was observed; however, cardiac expression of the atrial natriuretic peptide was increased on messenger RNA (3.6-fold, P < 0.05) and protein level (3.1-fold, P < 0.05). Following Shunt, left ventricular dilation and hypertrophy were similar in ERK2tg mice and WT littermates. Left ventricular function was maintained, and changes in gene expression indicated reactivation of the foetal gene program in both genotypes. No differences in cardiac fibrosis and kinase activation was found amongst all experimental groups, whereas apoptosis was similarly increased through Shunt in ERK2tg and WT mice.
VO-induced eccentric hypertrophy is associated with reduced cardiac ERK1/2 activation in vivo. Cardiomyocyte-specific overexpression of ERK2, however, does not alter cardiac remodelling during VO. Future studies need to define the pathophysiological relevance of decreased ERK1/2 signalling during VO.
容量超负荷（VO）和压力超负荷（PO）引起不同的心脏重塑反应，包括不同的信号通路。细胞外信号调节激酶 1 和 2（ERK1/2）是丝裂原激活蛋白激酶（MAPK）途径中的关键信号成分，调节压力超负荷（PO）时的心脏重塑。本研究旨在评估它们在 VO 诱导的心脏重塑中的作用，因为这一点尚不清楚。
在小鼠中进行腹主动脉-腔静脉瘘（Shunt）手术以诱导心脏 VO。两周的 Shunt 导致野生型（WT）小鼠心脏 ERK1/2 激活显著减少，表现为 TEY（Thr-Glu-Tyr）基序磷酸化减少（与 Sham 对照组相比减少 28%，P < 0.05）。其他 MAPKs 的磷酸化不受影响。为了进一步评估，研究了心肌细胞特异性 ERK2 过表达（ERK2tg）的转基因小鼠。在基线时，与 WT 同窝仔相比，ERK2tg 小鼠的心脏 ERK1/2 磷酸化保持不变，并且没有明显的心脏表型观察到；然而，心房利钠肽的信使 RNA（3.6 倍，P < 0.05）和蛋白水平（3.1 倍，P < 0.05）表达增加。在 Shunt 后，ERK2tg 小鼠和 WT 同窝仔的左心室扩张和肥大相似。左心室功能得以维持，基因表达的变化表明两种基因型中胎儿基因程序的重新激活。在所有实验组中，心脏纤维化和激酶激活没有差异，而通过 Shunt，ERK2tg 和 WT 小鼠的凋亡同样增加。
VO 诱导的偏心性肥大与体内心脏 ERK1/2 激活减少有关。然而，心肌细胞特异性过表达 ERK2 不会改变 VO 期间的心脏重塑。未来的研究需要确定 VO 期间 ERK1/2 信号减少的病理生理相关性。
