Inhibition of calpain reduces oxidative stress and attenuates endothelial dysfunction in diabetes.
Inhibition of calpain reduces oxidative stress and attenuates endothelial dysfunction in diabetes.
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DOI：
10.1186/1475-2840-13-88
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发表时间：
2014-05-03
影响因子：
9.3
通讯作者：
Peng T
中科院分区：
文献类型：
--
作者：
Chen B;Zhao Q;Ni R;Tang F;Shan L;Cepinskas I;Cepinskas G;Wang W;Schiller PW;Peng T
本研究旨在探讨在糖尿病实验条件下，钙蛋白酶在内皮细胞产生活性氧(ROS)和内皮依赖性血管功能障碍中的作用。高糖刺激人脐静脉内皮细胞(HUVECs)钙激活蛋白，诱导细胞凋亡，减少一氧化氮(NO)的产生，但不改变eNOS蛋白的表达、磷酸化和二聚体的形成。高糖的这些效应与细胞内ROS的产生和线粒体超氧化物的产生有关。选择性清除线粒体超氧化物增加了高糖刺激的HUVECs中NO的产生。通过抑制钙蛋白酶的过度表达或药理钙蛋白酶抑制剂可阻止高糖诱导的ROS生成、线粒体超氧化物歧化和细胞凋亡，这些都与HUVECs NO生成的增加是同步的。在链脲佐菌素诱导的1型糖尿病小鼠模型和OVE26 1型糖尿病小鼠模型中，钙蛋白酶的激活与主动脉中ROS产生和过氧亚硝酸盐形成的增加相关。转基因过表达calastatin可减少糖尿病小鼠体内ROS的产生和过氧亚硝酸盐的形成。同时，在糖尿病小鼠模型中，由糖尿病引起的主动脉环内皮依赖性松弛的减少可被过度表达的钙糊蛋白逆转。然而，内皮型一氧化氮合酶基因的缺失取消了卡巴斯丁对糖尿病小鼠血管内皮依赖性松弛的保护作用。本研究提示，Calain可能在糖尿病血管内皮细胞ROS的产生和内皮依赖性功能障碍中发挥作用。因此，Calain可能是克服糖尿病所致血管功能障碍的重要治疗靶点。
The present study was to investigate the role of calpain in reactive oxygen species (ROS) production in endothelial cells and endothelium-dependent vascular dysfunction under experimental conditions of diabetes. Exposure to high glucose activated calpain, induced apoptosis and reduced nitric oxide (NO) production without changing eNOS protein expression, its phosphorylation and dimers formation in primary human umbilical vein endothelial cells (HUVECs). These effects of high glucose correlated with intracellular ROS production and mitochondrial superoxide generation. Selectively scavenging mitochondrial superoxide increased NO production in high glucose-stimulated HUVECs. Inhibition of calpain using over-expression of calpastatin or pharmacological calpain inhibitor prevented high glucose-induced ROS production, mitochondrial superoxide generation and apoptosis, which were concurrent with an elevation of NO production in HUVECs. In mouse models of streptozotocin-induced type-1 diabetes and OVE26 type-1 diabetic mice, calpain activation correlated with an increase in ROS production and peroxynitrite formation in aortas. Transgenic over-expression of calpastatin reduced ROS production and peroxynitrite formation in diabetic mice. In parallel, diabetes-induced reduction of endothelium-dependent relaxation in aortic ring was reversed by over-expression of calpastatin in mouse models of diabetes. However, the protective effect of calpastatin on endothelium-dependent relaxation was abrogated by eNOS deletion in diabetic mice. This study suggests that calpain may play a role in vascular endothelial cell ROS production and endothelium-dependent dysfunction in diabetes. Thus, calpain may be an important therapeutic target to overcome diabetes-induced vascular dysfunction.
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影响因子：
8.2
作者：
Cifarelli, V.;Geng, X.;Luppi, P.
通讯作者：
Luppi, P.
影响因子：
4.8
作者：
Jahani-Asl, Arezu;Pilon-Larose, Karine;Slack, Ruth S.
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影响因子：
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作者：
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Dikalov, Sergey
DOI：
10.1152/ajpheart.00377.2006
发表时间：
2006-12-01
影响因子：
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作者：
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影响因子：
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作者：
Lau, Yeh Siang;Tian, Xiao Yu;Mustafa, Mohd Rais
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