Cyclic strain modulates resistance to oxidant stress by increasing G6PDH expression in smooth muscle cells
Cyclic strain modulates resistance to oxidant stress by increasing G6PDH expression in smooth muscle cells
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DOI：
10.1152/ajpheart.2000.279.5.h2477
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发表时间：
2000-11-01
影响因子：
4.8
通讯作者：
Loscalzo, J
中科院分区：
文献类型：
--
作者：
Leopold, JA;Loscalzo, J
血管平滑肌细胞（VSMC）可能会受到机械力，如周期性应变，促进活性氧（ROS）的形成。我们假设VSMC通过增加葡萄糖-6-磷酸脱氢酶（G6 PDH）的表达来调节这种不利的环境，以维持或恢复细胞内谷胱甘肽（GSH）水平。循环应变增加超氧化物的形成，这导致减少GSH，因为氧化型谷胱甘肽的形成增加，也有谷胱甘肽过氧化物酶和谷胱甘肽还原酶的活动增加。G6 PDH活性和蛋白表达增强伴随GSH水平的降低，并保持升高，直到细胞内GSH水平恢复。为了证实G6 PDH在补充GSH储存中的作用，我们用DHEA抑制G6 PDH活性或用反义寡核苷酸抑制酶表达。G6 PDH活性或表达减少与持续耗竭GSH水平和抑制循环菌株介导的谷胱甘肽还原酶活性增加有关。这些观察结果表明，循环应变促进氧化应激VSMC，这反过来又诱导G6 PDH的表达。当G6 PDH被抑制时，由于谷胱甘肽还原酶活性受损，GSH水平不能恢复。这些数据表明，G6 PDH是一个关键的决定因素，在VSMC氧化应激的反应。
Vascular smooth muscle cells (VSMC) may be subjected to mechanical forces, such as cyclic strain, that promote the formation of reactive oxygen species (ROS). We hypothesized that VSMC modulate this adverse milieu by increasing the expression of glucose-6-phosphate dehydrogenase (G6PDH) to maintain or restore intracellular glutathione (GSH) levels. Cyclic strain increased superoxide formation, which resulted in diminished GSH because of an increase in oxidized glutathione formation; there was also an increase in glutathione peroxidase and glutathione reductase activities. G6PDH activity and protein expression were enhanced concomitant with decreases in GSH levels and remained elevated until intracellular GSH levels were restored. To confirm the role of G6PDH in repleting GSH stores, we inhibited G6PDH activity with DHEA or inhibited enzyme expression with an antisense oligodeoxynucleotide. Diminished G6PDH activity or expression was associated with persistently depleted GSH levels and inhibition of the cyclic strain-mediated increase in glutathione reductase activity. These observations demonstrate that cyclic strain promotes oxidant stress in VSMC, which, in turn, induces G6PDH expression. When G6PDH is inhibited, GSH levels are not restored because of impaired glutathione reductase activity. These data suggest that G6PDH is a critical determinant of the response to oxidant stress in VSMC.