Apoptosis signal-regulating kinase 1 mediates cellular senescence induced by high glucose in endothelial cells
Apoptosis signal-regulating kinase 1 mediates cellular senescence induced by high glucose in endothelial cells
复制标题
DOI：
10.2337/db05-1607
复制
发表时间：
2006-06-01
期刊：
影响因子：
7.7
通讯作者：
Ogihara, Toshio
中科院分区：
文献类型：
--
作者：
Yokoi, Toyohiko;Fukuo, Keisuke;Ogihara, Toshio
糖尿病患者的血管老化加速。然而，其潜在机制仍不清楚。在这里，我们发现高糖诱导凋亡信号调节激酶1（ASK 1.）的激活，一种介导高血糖诱导的内皮细胞衰老的衰老诱导信号。高糖诱导人脐静脉内皮细胞（HUVECs）中ASK 1表达水平及其活性呈时间依赖性增加。内皮细胞与高糖孵育增加了表达衰老相关β-半乳糖苷酶（SA-β-gal）活性的细胞比例。然而，转染腺病毒构建体，包括显性阴性形式的ASK 1基因显着抑制SA-β-半乳糖活性诱导的高糖。此外，用表达组成型活性ASK 1基因的腺病毒构建体感染直接诱导SA-R-gal活性水平的增加。ASK 1信号的激活也增强了HUVECs中纤溶酶原激活物抑制剂-1（派-1）的表达。在链脲佐菌素（STZ）糖尿病小鼠中观察到血管内皮细胞衰老和血浆派-1水平升高的诱导，而在ASK 1基因敲除小鼠中STZ诱导的这些变化减弱。我们的研究结果表明，高血糖加速内皮细胞衰老和上调派-1的表达，通过激活ASK 1信号。因此，ASK 1.可能是预防糖尿病患者血管老化和血栓形成的新治疗靶点。
Vascular ageing is accelerated in patients with diabetes. However, the underlying mechanism remains unclear. Here, we show that high glucose induces activation of apoptosis signal-regulating kinase 1 (ASK1.), an apoptosis-inducing signal that mediates endothelial cell senescence induced by hyperglycemia. High glucose induced a time-dependent increase in the levels of ASK1 expression and its activity in human umbilical vein endothelial cells (HUVECs). Incubation of endothelial cells with high glucose increased the proportion of cells expressing senescence-associated beta-galactosidase (SA-beta-gal) activity. However, transfection with an adenoviral construct including a dominant negative form of ASK1 gene significantly inhibited SA-beta-gal activity induced by high glucose. In addition, infection with an adenoviral construct expressing the constitutively active ASK1 gene directly induced an increase in the levels of SA-R-gal activity. Activation of the ASK1 signal also enhanced plasminogen activator inhibitor-1 (PAI-1) expression in HUVECs. Induction of senescent endothelial cells in aortas and elevation of plasma PAI-1 levels were observed in streptozotocin (STZ) diabetic mice, whereas these changes induced by STZ were attenuated in ASK1-knockout mice. Our results suggest that hyperglycemia accelerates endothelial cell senescence and upregulation of PAI-1 expression through activation of the ASK1 signal. Thus, ASK1. may be a new therapeutic target to prevent vascular ageing and thrombosis in diabetic patients.