2018 ESC/ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension
2018 ESC/ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension
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DOI：
10.1097/hjh.0000000000001940
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发表时间：
2018-10-01
影响因子：
4.9
通讯作者：
Desormais, Ileana
中科院分区：
文献类型：
--
作者：
Williams, Bryan;Mancia, Giuseppe;Desormais, Ileana
目的内质网应激时细胞凋亡调控基因GADD153(生长停滞和DNA损伤诱导基因153)的表达增加。机械拉伸如何影响血管平滑肌细胞(VSMCs)中GADD153在细胞凋亡过程中的调节尚不完全清楚。我们的目的是验证机械拉伸诱导VSMCs凋亡的GADD153表达的假设。方法和结果生长在柔性膜上的大鼠VSMCs在真空中以60次/min的速度拉伸到最大伸长率的20%。采用成年大鼠主动脉-腔静脉分流术模型，观察GADD153的表达。循环牵张后18h，GADD153蛋白和mRNA的表达显著增加。拉伸前30min加入c-jun氨基末端激酶抑制剂SP600125、JNKsiRNA、肿瘤坏死因子-α和肿瘤坏死因子-α受体抗体可抑制GADD153蛋白的表达。凝胶漂移实验显示，拉伸后激活因子1(AP-1)的DNA结合活性增加。SP600125、JNKsiRNA和肿瘤坏死因子-α抗体可阻断拉伸诱导的结合活性。当GADD153-Mut、SP600125和c-jun抗体取消启动子活性时，Stretch增加。拉伸后的VSMC条件培养液和未拉伸的VSMC加入外源性肿瘤坏死因子-α重组蛋白后，GADD153蛋白的表达与拉伸后相似。在成年大鼠主动脉-腔静脉分流的活体模型中，GADD153蛋白的表达也增加。结论循环牵张增强了培养的大鼠VSMCs中GADD153的表达。牵张诱导的GADD153是由肿瘤坏死因子-α介导的，至少部分是通过JNK和AP-1途径。这些发现表明GADD153在牵张诱导的VSMC凋亡中起作用。
AimsThe expression of GADD153 (growth arrest and DNA damage-inducible gene 153), an apoptosis-regulated gene, increases during endoplasmic reticulum (ER) stress. How mechanical stretch affects the regulation of GADD153 in vascular smooth muscle cells (VSMCs) during apoptosis is not fully understood. We aimed to test the hypothesis that mechanical stretch induces GADD153 expression in VSMCs undergoing apoptosis.Methods and resultsRat VSMCs grown on a flexible membrane base were stretched by vacuum to 20% of maximum elongation, at 60 cycles/min. Anin vivomodel of aorta-caval shunt in adult rats was used to investigate GADD153 expression. Cyclic stretch significantly increased GADD153 protein and mRNA expression after 18 h of stretch. Addition of c-jun N-terminal kinase (JNK) inhibitor SP600125, JNK siRNA, tumour necrosis factor-α (TNF-α) and TNF-α receptor antibody 30 min before stretch inhibited the induction of GADD153 protein. Gel shift assay showed that DNA-binding activity of activating factor 1 (AP-1) increased after stretch. SP600125, JNK siRNA and TNF-α antibody abolished the binding activity induced by stretch. Stretch increased while GADD153-Mut plasmid, SP600125, and c-jun antibody abolished the promoter activity. Both conditioned media from stretched VSMCs and exogenous administration of TNF-α recombinant protein to the non-stretched VSMCs increased GADD153 protein expression similar to that seen after stretch. Anin vivomodel of aorta-caval shunt in adult rats also demonstrated the increased GADD153 protein expression in the aorta.ConclusionCyclic stretch enhanced GADD153 expression in cultured rat VSMCs. The stretch-induced GADD153 is mediated by TNF-α, at least in part, through the JNK and AP-1 pathway. These findings suggest that GADD153 plays a role in stretch-induced VSMC apoptosis.