Xing Hang, Zhang Zhiqi, Shi Guangbin, He Yixin, Song Yi, Liu Yuhong, Harrington Elizabeth O, Sellke Frank W, Feng Jun
Cardiothoracic Surgery Research Laboratory, Cardiovascular Research Center, Department of Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, United States.
Vascular Research Laboratory, Providence VA Medical Center, Department of Medicine, Alpert Medical School of Brown University, Providence, RI, United States.
Front Cell Dev Biol. 2021 Feb 18;9:643810. doi: 10.3389/fcell.2021.643810. eCollection 2021.
Diabetes is associated with coronary endothelial dysfunction. Persistent oxidative stress during diabetes contributes to coronary endothelial dysfunction. The mitochondria are main sources of reactive oxygen species (ROS) in diabetes, and mitochondria-targeted antioxidant mito-Tempo can prevent mitochondrial reactive oxygen species (mROS) generation in a variety of disorders. Inhibition/inactivation of small-conductance Ca-activated K (SK) channels contribute to diabetic downregulation of coronary endothelial function/relaxation. However, few investigated the role of mROS on endothelial dysfunction/vasodilation and endothelial SK channel downregulation in diabetes. The aim of present study was to investigate the chronic administration of mito-Tempo, on coronary vasodilation, and endothelial SK channel activity of mice with or without diabetes. Mito-Tempo (1 mg/kg/day) was applied to the mice with or without diabetes ( = 10/group) for 4 weeks. relaxation response of pre-contracted arteries was examined in the presence or absence of the vasodilatory agents. SK channel currents of the isolated mouse heart endothelial cells were measured using whole-cell patch clamp methods. At baseline, coronary endothelium-dependent relaxation responses to ADP and the selective SK channel activator NS309 and endothelial SK channel currents were decreased in diabetic mice compared with that in non-diabetic (ND) mice ( < 0.05). After a 4-week treatment with mito-Tempo, coronary endothelium-dependent relaxation response to ADP or NS309 and endothelial SK channel currents in the diabetic mice was significantly improved when compared with that in untreated diabetic mice ( < 0.05). Interestingly, coronary relaxation responses to ADP and NS309 and endothelial SK channel currents were not significantly changed in ND mice after mito-Tempo treatment, as compared to that of untreated control group. Chronic inhibition of endothelial mROS appears to improve coronary endothelial function/dilation and SK channel activity in diabetes, and mROS inhibitors may be a novel strategy to treat vascular complications in diabetes.
糖尿病与冠状动脉内皮功能障碍有关。糖尿病期间持续的氧化应激会导致冠状动脉内皮功能障碍。线粒体是糖尿病中活性氧（ROS）的主要来源，而线粒体靶向抗氧化剂米托坦能在多种疾病中防止线粒体活性氧（mROS）的产生。小电导钙激活钾（SK）通道的抑制/失活会导致糖尿病患者冠状动脉内皮功能/舒张功能下调。然而，很少有人研究mROS在糖尿病内皮功能障碍/血管舒张以及内皮SK通道下调中的作用。本研究的目的是调查长期给予米托坦对糖尿病和非糖尿病小鼠冠状动脉舒张以及内皮SK通道活性的影响。将米托坦（1毫克/千克/天）给予糖尿病和非糖尿病小鼠（每组n = 10），持续4周。在有或没有血管舒张剂的情况下，检测预收缩动脉的舒张反应。使用全细胞膜片钳方法测量分离的小鼠心脏内皮细胞的SK通道电流。在基线时，与非糖尿病（ND）小鼠相比，糖尿病小鼠对ADP和选择性SK通道激活剂NS309的冠状动脉内皮依赖性舒张反应以及内皮SK通道电流降低（P < 0.05）。用米托坦治疗4周后，与未治疗的糖尿病小鼠相比，糖尿病小鼠对ADP或NS309的冠状动脉内皮依赖性舒张反应以及内皮SK通道电流显著改善（P < 0.05）。有趣的是，与未治疗的对照组相比，米托坦治疗后ND小鼠对ADP和NS309的冠状动脉舒张反应以及内皮SK通道电流没有显著变化。长期抑制内皮mROS似乎可以改善糖尿病患者的冠状动脉内皮功能/舒张和SK通道活性，mROS抑制剂可能是治疗糖尿病血管并发症的新策略。
