Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, 1819 West Polk St., M/C 640, Chicago, IL 60612, USA.
Am J Physiol Cell Physiol. 2012 Nov 15;303(10):C1055-60. doi: 10.1152/ajpcell.00087.2012. Epub 2012 Sep 12.
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 Ca(2+) concentration and VDAC protein levels than control MCECs. The expression of VDAC-short hairpin RNA (shRNA) not only decreased the resting mitochondrial Ca(2+) concentration but also attenuated mitochondrial Ca(2+) uptake in diabetic MCECs. Furthermore, the downregulation of VDAC in diabetic MCECs significantly decreased mitochondrial superoxide anion (O(2)(-)) 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 Ca(2+) concentration, mitochondrial O(2)(-) 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.
由于心脏内皮细胞凋亡增加导致的毛细血管密度降低与糖尿病中的心肌缺血有关。电压依赖性阴离子通道（VDAC）在调节线粒体代谢功能和线粒体介导的细胞凋亡中起着至关重要的作用。本研究旨在研究 VDAC 在糖尿病中冠状动脉内皮功能障碍中的作用。糖尿病小鼠的左心室和从糖尿病小鼠中分离出的鼠冠状动脉内皮细胞（MCEC）中的内皮细胞凋亡更多，与对照 MCEC 相比，糖尿病 MCEC 中的线粒体 Ca(2+)浓度和 VDAC 蛋白水平显著更高。VDAC-short hairpin RNA（shRNA）的表达不仅降低了静息状态下的线粒体 Ca(2+)浓度，而且还减弱了糖尿病 MCEC 中线粒体 Ca(2+)的摄取。此外，糖尿病 MCEC 中 VDAC 的下调显著降低了线粒体超氧阴离子（O(2)(-)）的产生和线粒体通透性转换孔（mPTP）的开放（细胞凋亡的间接指标）至对照水平。这些数据表明，糖尿病 MCEC 中 VDAC 水平的增加导致线粒体 Ca(2+)浓度、线粒体 O(2)(-)生成和 mPTP 开放活性增加。正常化 VDAC 蛋白水平可能有助于减少内皮细胞凋亡、增加心脏中的毛细血管密度，并随后降低糖尿病中的心肌缺血发生率。
