Failure of Isoflurane Cardiac Preconditioning in Obese Type 2 Diabetic Mice Involves Aberrant Regulation of MicroRNA-21, Endothelial Nitric-oxide Synthase, and Mitochondrial Complex I.
Failure of Isoflurane Cardiac Preconditioning in Obese Type 2 Diabetic Mice Involves Aberrant Regulation of MicroRNA-21, Endothelial Nitric-oxide Synthase, and Mitochondrial Complex I.
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肥胖 2 型糖尿病小鼠异氟烷心脏预处理失败涉及 microRNA-21、内皮一氧化氮合酶和线粒体复合物 I 的异常调节
DOI：
10.1097/aln.0000000000001926
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发表时间：
2018-01
期刊：
影响因子：
8.8
通讯作者：
Liang M
中科院分区：
文献类型：
--
作者：
Ge ZD;Li Y;Qiao S;Bai X;Warltier DC;Kersten JR;Bosnjak ZJ;Liang M
糖尿病损害了挥发性麻醉药的心脏保护作用，但其机制仍然不清楚。我们研究了异氟烷对II型糖尿病小鼠microRNA-21、内皮型一氧化氮合酶和线粒体呼吸复合物I的调节作用。在存在或不存在缺血前给予异氟烷的情况下，在肥胖2型糖尿病（db/db）小鼠和C57 BL/6对照小鼠中离体产生心肌缺血/再灌注损伤。通过实时定量逆转录聚合酶链反应定量心脏microRNA-21。Western blot分析内皮型一氧化氮合酶的二聚体和单体。线粒体烟酰胺腺嘌呤二核苷酸荧光测定Langendorff灌注心脏。db/db小鼠的体重和空腹血糖高于C57 BL/6小鼠。异氟烷使左心室舒张末期压从对照组的35±8 mmHg降低至23±9 mmHg（P=0.019，n=8只小鼠/组，平均值± SD），并在C57 BL/6小鼠缺血再灌注后2 h升高±dP/dt。异氟烷的这些有益作用在db/db小鼠中丧失。在C57 BL/6小鼠中，异氟烷升高了microRNA-21和内皮型一氧化氮合酶二聚体/单体的比率，并在缺血后5分钟降低了线粒体烟酰胺腺嘌呤二核苷酸水平，但对db/db小鼠无影响。microRNA-21敲除可阻断异氟烷的这些有利作用，而内皮一氧化氮合酶敲除对microRNA-21的表达没有影响，但可阻断异氟烷预处理对烟酰胺腺嘌呤二核苷酸的抑制作用。肥胖II型糖尿病db/db小鼠异氟烷心脏预处理失败与microRNA-21、内皮型一氧化氮合酶和线粒体呼吸复合物I的异常调节相关
Diabetes impairs the cardioprotective effect of volatile anesthetics, yet the mechanisms are still murky. We examined the regulatory effect of isoflurane on microRNA-21, endothelial nitric oxide synthase, and mitochondrial respiratory complex I in type II diabetic mice. Myocardial ischemia/reperfusion injury was produced in obese type 2 diabetic (db/db) and C57BL/6 control mice ex vivo in the presence or absence of isoflurane administered prior to ischemia. Cardiac microRNA-21 was quantified by real-time quantitative reverse transcriptional-polymerase chain reaction. The dimers and monomers of endothelial nitric oxide synthase were measured by Western blot analysis. Mitochondrial nicotinamide adenine dinucleotide fluorescence was determined in Langendorff-perfused hearts. Body weight and fasting blood glucose were greater in db/db than C57BL/6 mice. Isoflurane decreased left ventricular end-diastolic pressure from 35±8 mmHg in control to 23±9 mmHg (P=0.019, n=8 mice/group, mean ± SD) and elevated ±dP/dt 2 h after post-ischemic reperfusion in C57BL/6 mice. These beneficial effects of isoflurane were lost in db/db mice. Isoflurane elevated microRNA-21 and the ratio of endothelial nitric oxide synthase dimers/monomers and decreased mitochondrial nicotinamide adenine dinucleotide levels 5 min after ischemia in C57BL/6 but not db/db mice. MicroRNA-21 knockout blocked these favorable effects of isoflurane, whereas endothelial nitric oxide synthase knockout had no effect on the expression of microRNA-21 but blocked the inhibitory effect of isoflurane preconditioning on nicotinamide adenine dinucleotide. Failure of isoflurane cardiac preconditioning in obese type II diabetic db/db mice is associated with aberrant regulation of microRNA-21, endothelial nitric oxide synthase, and mitochondrial respiratory complex I.