Dynamin-related protein 1 mediates low glucose-induced endothelial dysfunction in human arterioles.
Dynamin-related protein 1 mediates low glucose-induced endothelial dysfunction in human arterioles.
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DOI：
10.1152/ajpheart.00499.2016
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发表时间：
2017-03
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通讯作者：
Michael J. Tanner;Jingli Wang;Rong Ying;Tisha B. Suboc;Mobin Malik;A. Couillard;Amberly Branum;V. Puppala;Michael E. Widlansky
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作者：
Michael J. Tanner;Jingli Wang;Rong Ying;Tisha B. Suboc;Mobin Malik;A. Couillard;Amberly Branum;V. Puppala;Michael E. Widlansky
强化的血糖调节导致低血糖发生率增加。低血糖负荷与不良的心血管并发症相关，并急性和慢性地导致内皮功能障碍。先前的数据表明，线粒体功能障碍有助于低血糖诱导的内皮功能障碍，但这种联系背后的机制仍不清楚。我们试图确定临床相关的低糖(LG)暴露是否通过激活线粒体分裂过程而急性地导致内皮功能障碍。用共聚焦显微镜观察培养内皮细胞线粒体的形态。本研究以人离体小动脉为研究对象，探讨LG诱导的线粒体分裂对有害活性氧(ROS)的形成、一氧化氮(NO)的生物利用度和内皮依赖性血管松弛的影响。用荧光显微镜观察线粒体ROS和NO水平的变化，用视频显微镜测量血管扩张反应。在LG暴露期间用MDVI-1药物阻断分泌蛋白DRP1可减少血管内皮细胞线粒体断裂(LG：0.469；LG+MDVI-1：0.276；P=0.003)，阻止血管ROS的形成(LG：2.036；LG+MDVI-1：1.774；P=0.005)，增加NO的存在(LG：1.352；LG+MDVI-1：1.502；P=0.048)，并改善对乙酰胆碱的血管扩张反应(LG：31.6%；LG+Mdivi-1；最大剂量时为78.5%；P<；0.001)。此外，在LG条件下，通过siRNA敲除减少Drp1的表达也改善了血管松弛。暴露于LG可导致内皮功能障碍，并伴随分离的人小动脉线粒体表型的改变。DRp1的破坏和随后的线粒体碎裂事件防止受损的血管扩张，恢复线粒体表型，并暗示线粒体分裂是LG诱导的内皮功能障碍的主要媒介。新和值得注意的急性低糖暴露通过DRp1诱导内皮细胞线粒体碎裂，并与人小动脉的内皮功能受损有关。靶向DRP1可防止碎裂，改善血管功能，并可能为改善糖尿病患者的心血管并发症提供治疗靶点。请收听本文相应的播客@http://ajpheart.podbean.com/e/mitochondrial-dynamics-impact-endothelial-function/.
Intensive glycemic regulation has resulted in an increased incidence of hypoglycemia. Hypoglycemic burden correlates with adverse cardiovascular complications and contributes acutely and chronically to endothelial dysfunction. Prior data indicate that mitochondrial dysfunction contributes to hypoglycemia-induced endothelial dysfunction, but the mechanisms behind this linkage remain unknown. We attempt to determine whether clinically relevant low-glucose (LG) exposures acutely induce endothelial dysfunction through activation of the mitochondrial fission process. Characterization of mitochondrial morphology was carried out in cultured endothelial cells by using confocal microscopy. Isolated human arterioles were used to explore the effect LG-induced mitochondrial fission has on the formation of detrimental reactive oxygen species (ROS), bioavailability of nitric oxide (NO), and endothelial-dependent vascular relaxation. Fluorescence microscopy was employed to visualize changes in mitochondrial ROS and NO levels and videomicroscopy applied to measure vasodilation response. Pharmacological disruption of the profission protein Drp1 with Mdivi-1 during LG exposure reduced mitochondrial fragmentation among vascular endothelial cells (LG: 0.469; LG+Mdivi-1: 0.276; P = 0.003), prevented formation of vascular ROS (LG: 2.036; LG+Mdivi-1: 1.774; P = 0.005), increased the presence of NO (LG: 1.352; LG+Mdivi-1: 1.502; P = 0.048), and improved vascular dilation response to acetylcholine (LG: 31.6%; LG+Mdivi-1; 78.5% at maximum dose; P < 0.001). Additionally, decreased expression of Drp1 via siRNA knockdown during LG conditions also improved vascular relaxation. Exposure to LG imparts endothelial dysfunction coupled with altered mitochondrial phenotypes among isolated human arterioles. Disruption of Drp1 and subsequent mitochondrial fragmentation events prevents impaired vascular dilation, restores mitochondrial phenotype, and implicates mitochondrial fission as a primary mediator of LG-induced endothelial dysfunction.NEW & NOTEWORTHY Acute low-glucose exposure induces mitochondrial fragmentation in endothelial cells via Drp1 and is associated with impaired endothelial function in human arterioles. Targeting of Drp1 prevents fragmentation, improves vasofunction, and may provide a therapeutic target for improving cardiovascular complications among diabetics.Listen to this article's corresponding podcast @ http://ajpheart.podbean.com/e/mitochondrial-dynamics-impact-endothelial-function/.