Liu Yuhong, Kabakov Anatoli Y, Xie An, Shi Guangbin, Singh Arun K, Sodha Neel R, Ehsan Afshin, Usheva Anny, Agbortoko Vahid, Koren Gideon, Dudley Samuel C, Sellke Frank W, Feng Jun
Division of Cardiothoracic Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, United States of America.
Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, United States of America.
Int J Cardiol. 2020 Aug 1;312:1-9. doi: 10.1016/j.ijcard.2020.03.028. Epub 2020 Mar 12.
Diabetic (DM) inactivation of small conductance calcium-activated potassium (SK) channels contributes to coronary endothelial dysfunction. However, the mechanisms responsible for this down-regulation of endothelial SK channels are poorly understood. Thus, we hypothesized that the altered metabolic signaling in diabetes regulates endothelial SK channels and human coronary microvascular function.
Human atrial tissue, coronary arterioles and coronary artery endothelial cells (HCAECs) obtained from DM and non-diabetic (ND) patients (n = 12/group) undergoing cardiac surgery were used to analyze metabolic alterations, endothelial SK channel function, coronary microvascular reactivity and SK gene/protein expression/localization.
The relaxation response of DM coronary arterioles to the selective SK channel activator SKA-31 and calcium ionophore A23187 was significantly decreased compared to that of ND arterioles (p < 0.05). Diabetes increases the level of NADH and the NADH/NAD ratio in human myocardium and HCAECs (p < 0.05). Increase in intracellular NADH (100 μM) in the HCAECs caused a significant decrease in endothelial SK channel currents (p < 0.05), whereas, intracellular application of NAD (500 μM) increased the endothelial SK channel currents (p < 0.05). Mitochondrial reactive oxygen species (mROS) of HCAECs and NADPH oxidase (NOX) and PKC protein expression in the human myocardium and coronary microvasculature were increased respectively (p < 0.05).
Diabetes is associated with metabolic changes in the human myocardium, coronary microvasculature and HCAECs. Endothelial SK channel function is regulated by the metabolite pyridine nucleotides, NADH and NAD, suggesting that metabolic regulation of endothelial SK channels may contribute to coronary endothelial dysfunction in the DM patients with diabetes.
糖尿病（DM）导致小电导钙激活钾（SK）通道失活，这与冠状动脉内皮功能障碍有关。然而，内皮SK通道下调的机制尚不清楚。因此，我们推测糖尿病中代谢信号的改变调节了内皮SK通道和人冠状动脉微血管功能。
从接受心脏手术的糖尿病（DM）和非糖尿病（ND）患者（每组n = 12）获取人心房组织、冠状动脉小动脉和冠状动脉内皮细胞（HCAECs），用于分析代谢改变、内皮SK通道功能、冠状动脉微血管反应性以及SK基因/蛋白表达/定位。
与ND小动脉相比，DM冠状动脉小动脉对选择性SK通道激活剂SKA - 31和钙离子载体A23187的舒张反应显著降低（p < 0.05）。糖尿病会增加人心肌和HCAECs中NADH水平以及NADH/NAD比值（p < 0.05）。HCAECs中细胞内NADH增加（100 μM）会导致内皮SK通道电流显著降低（p < 0.05），而细胞内应用NAD（500 μM）则会增加内皮SK通道电流（p < 0.05）。HCAECs的线粒体活性氧（mROS）以及人心肌和冠状动脉微血管中的NADPH氧化酶（NOX）和PKC蛋白表达分别增加（p < 0.05）。
糖尿病与人心肌、冠状动脉微血管和HCAECs中的代谢变化有关。内皮SK通道功能受代谢物吡啶核苷酸NADH和NAD调节，这表明内皮SK通道的代谢调节可能导致糖尿病DM患者的冠状动脉内皮功能障碍。
