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首页> 外文期刊>Journal of Molecular and Cellular Cardiology >Interplay between the E2F pathway and beta-adrenergic signaling in the pathological hypertrophic response of myocardium
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Interplay between the E2F pathway and beta-adrenergic signaling in the pathological hypertrophic response of myocardium

机译：E2F途径与β-肾上腺素信号传导在心肌病理性肥厚反应中的相互作用

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The E2F/Pocket protein (Rb) pathway regulates cell growth, differentiation, and death by modulating gene expression. We previously examined this pathway in the myocardium via manipulation of the unique E2F repressor, E2F6, which is believed to repress gene activity independently of Rb. Mice with targeted expression of E2F6 in postnatal myocardium developed dilated cardiomyopathy (DCM) without hypertrophic growth. We assessed the mechanisms of the apparent failure of compensatory hypertrophic growth as well as their response to the beta-adrenergic agonist isoproterenol. As early as 2 weeks, E2F6 transgenic (Tg) mice present with dilated thinner left ventricles and significantly reduced ejection fraction and fractional shortening which persists at 6 weeks of age, but with no apparent increase in left ventricle weight: body weight (LVW:BW). E2F6-Tg mice treated with isoproterenol (6.1 mg/kg/day) show double the increase in LVW:BW than their Wt counterparts (32% vs 16%, p-value: 0.007). Western blot analysis revealed the activation of the adrenergic pathway in Tg heart tissue under basal conditions with similar to 2-fold increase in the level of beta(2)-adrenergic receptors (p-value: 8.9E-05), protein kinase A catalytic subunit (PKA-C) (p-value: 0.0176), activated c-Src tyrosine-protein kinase (p-value: 0.0002), extracellular receptor kinase 2 (ERK2) (p-value: 0.0005), and induction of the anti-apoptotic protein Bcl2 (p-value 0.0.00001). In contrast, a similar to 60% decrease in the cardiac growth regulator: AKT1 (p-value 0.0001) and a similar to four fold increase in cyclic AMP dependent phosphodiesterase 4D (PDE4D), the negative regulator of PICA activity, were evident in the myocardium of E2F6-Tg mice. The expression of E2F3 was down-regulated by E2F6, but was restored by isoproterenol. Further, Rb expression was down-regulated in Tg mice in response to isoproterenol implying a net activation of the E2F pathway. Thus the unique regulation of E2F activity by E2F6 renders the myocardium hypersensitive to adrenergic stimulus resulting in robust hypertrophic growth.
机译：E2F / Pocket蛋白（Rb）途径通过调节基因表达来调节细胞的生长，分化和死亡。我们先前通过操纵独特的E2F阻遏物E2F6来检查了心肌中的该途径，该E2F6被认为可以独立于Rb抑制基因活性。在产后心肌中具有E2F6靶向表达的小鼠发生了扩张型心肌病（DCM），而没有肥厚的生长。我们评估了明显的代偿性肥大生长失败的机制，以及它们对β-肾上腺素能激动剂异丙肾上腺素的反应。早在2周时，E2F6转基因（Tg）小鼠的左心室扩张变薄，并且射血分数和分数缩短明显降低，并持续到6周龄，但左心室重量：体重（LVW：BW）没有明显增加）。用异丙肾上腺素（6.1 mg / kg /天）处理的E2F6-Tg小鼠的LVW：BW增幅是Wt小鼠的两倍（32％对16％，p值：0.007）。蛋白质印迹分析显示，在基础条件下，Tg心脏组织中肾上腺素途径的激活与β（2）-肾上腺素受体的水平增加约2倍（p值：8.9E-05），蛋白激酶A催化亚基（PKA-C）（p值：0.0176），活化的c-Src酪氨酸蛋白激酶（p值：0.0002），细胞外受体激酶2（ERK2）（p值：0.0005）和抗-凋亡蛋白Bcl2（p值0.0.00001）。相反，心脏生长调节剂：AKT1（p值0.0001）下降约60％，环状AMP依赖性磷酸二酯酶4D（PDE4D）（PICA活性的负调节剂）下降约4倍。 E2F6-Tg小鼠的心肌。 E2F3的表达被E2F6下调，但被异丙肾上腺素恢复。此外，响应于异丙肾上腺素，Rb表达在Tg小鼠中被下调，这暗示着E2F途径的净激活。因此，E2F6对E2F活性的独特调节使心肌对肾上腺素能刺激高度敏感，从而导致强劲的肥大性生长。

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