VDAC: old protein with new roles in diabetes.
VDAC: old protein with new roles in diabetes.
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VDAC：旧蛋白质在糖尿病中发挥新作用。
DOI：
10.1152/ajpcell.00087.2012
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Makino,Ayako
中科院分区：
文献类型：
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作者：
Sasaki,Koh;Donthamsetty,Reshma;Heldak,Michael;Cho,Young-Eun;Scott,BrianT;Makino,Ayako
糖尿病心肌缺血与心脏内皮细胞凋亡增加导致的毛细血管密度降低有关。电压依赖性阴离子通道(VDAC)在线粒体代谢功能的调节和线粒体介导的细胞凋亡中起着重要作用。本研究旨在探讨VDAC在糖尿病冠状动脉内皮功能障碍中的作用。糖尿病小鼠左心室内皮细胞(ECs)凋亡明显增加，糖尿病小鼠冠状动脉内皮细胞(MCECs)线粒体钙离子浓度和VDAC蛋白水平明显高于对照组MCECs。VDAC-短发夹状RNA(ShRNA)的表达不仅降低了糖尿病大鼠肾小管上皮细胞线粒体静息状态下的钙离子浓度，而且还抑制了线粒体对钙的摄取。此外，糖尿病微血管内皮细胞中VDAC的下调显著降低了线粒体超氧阴离子(O2-−)的产生和线粒体通透性转换孔(MPTP)开放的活性(细胞凋亡的间接指标)，使其接近对照水平。这些数据提示糖尿病大鼠肾小管上皮细胞VDAC水平升高与线粒体钙离子浓度升高、线粒体O2-−生成增加和MPTP开放活性增加有关。VDAC蛋白水平正常化可能有助于减少血管内皮细胞凋亡，增加心脏毛细血管密度，从而降低糖尿病心肌缺血的发生率。
A decrease in capillary density due to an increase in endothelial cell apoptosis in the heart is implicated in cardiac ischemia in diabetes. The voltage-dependent anion channel (VDAC) plays a crucial role in the regulation of mitochondrial metabolic function and mitochondria-mediated apoptosis. This study is designed to examine the role of VDAC in coronary endothelial dysfunction in diabetes. Endothelial cells (ECs) were more apoptotic in diabetic left ventricle of diabetic mice and mouse coronary ECs (MCECs) isolated from diabetic mice exhibited significantly higher mitochondrial Ca2+concentration and VDAC protein levels than control MCECs. The expression of VDAC-short hairpin RNA (shRNA) not only decreased the resting mitochondrial Ca2+concentration but also attenuated mitochondrial Ca2+uptake in diabetic MCECs. Furthermore, the downregulation of VDAC in diabetic MCECs significantly decreased mitochondrial superoxide anion (O2−) production and the activity of the mitochondrial permeability transition pore (mPTP) opening (an indirect indicator of cell apoptosis) toward control levels. These data suggest that the increased VDAC level in diabetic MCECs is responsible for increased mitochondrial Ca2+concentration, mitochondrial O2−production, and mPTP opening activity. Normalizing VDAC protein level may help to decrease endothelial cell apoptosis, increase capillary density in the heart, and subsequently decrease the incidence of cardiac ischemia in diabetes.