上调血红素氧合酶1对糖尿病大鼠心功能的影响及可能机制  

Effects and mechanism of up-regulation of heme oxygenase-1 on cardiac function in diabetic rats

作　　者：刘璐[1] 曹剑[1] 李健[1] 陈天萌[1] 陈德友[1] 高进辽[1] 郭玉松[1] 范利[1] 

机构地区：[1]解放军总医院南楼心血管一科,北京100853

出　　处：《解放军医学院学报》2014年第12期1237-1240,1244,共5页Academic Journal of Chinese PLA Medical School

基　　金：北京市自然科学基金项目(7122175)~~

摘　　要：目的探讨上调血红素氧合酶1(heme oxygenase-1,HO-1)对糖尿病大鼠心脏功能的影响及可能机制。方法将48只Wistar大鼠随机分为对照组(A组,16只),糖尿病大鼠组(B组,16只),应用钴原卟啉Co PP(HO-1诱导剂)上调HO-1的糖尿病大鼠组(C组,16只)。测量各组大鼠尾静脉葡萄糖、胰岛素及脂联素水平,采用Langendorff装置测量各组大鼠心肌和冠脉功能,采用色谱技术测量心肌组织中丙二醛(malondialdehyde,MDA)、丙二酰辅酶A及乙酰辅酶A的含量,液体闪烁计数器测量心肌中超氧化物水平,采用免疫印迹法测定心脏裂解液中信号分子、一氧化氮合酶(诱导型一氧化氮合酶i NOS和内皮型一氧化氮合酶e NOS)活性及HO活性水平。结果糖尿病大鼠组葡萄糖水平显著高于对照组(P<0.01),而胰岛素水平、脂联素水平显著低于对照组(P<0.01,P<0.05),应用Co PP后C组的葡萄糖水平及脂联素水平均升高(P<0.05,P<0.01)。糖尿病大鼠离体心脏Langendorff灌注模型的左心室功能较对照组有所下降,而冠脉阻力(coronary resistance,CR)明显升高。而上调HO-1后,糖尿病大鼠的心脏功能显著升高(P<0.01)且CR明显降低(P<0.01)。上调HO-1后,糖尿病动物体内的HO-1蛋白水平升高并伴有心脏超氧化物O2-和丙二醛水平的显著降低(P<0.05)。另外,糖尿病大鼠体内信号分子明显降低(P<0.05),上调HO-1后显著升高(P<0.05)。结论上调血红素氧合酶1可抑制氧化应激反应,恢复e NOS/i NOS平衡,升高HO-1水平,提高内皮功能和胰岛素敏感性,达到了改善心肌功能和冠脉灌注效果的目的。Objective To investigate the effects and mechanism of up-regulation of heme oxygenase-1 （HO-1） on cardiac function of diabetic rats. Methods Forty-eight wistar rats were divided into 3 groups： control group （group A, n=16）, diabetic group （group B, n=16） and diabetic rats treated with HO-1 inducer cobalt-protoporphyrin IX （CoPP） to enhance HO-1 expression group （group C, n=16）. Tail vein blood samples of glucose, insulin and adiponectin were measured in each group. Isolated hearts were prepared to measure the cardiac and coronary functions. Levels of malondialdehyde （MDA）, malonyl coenzyme A （malonyl-CoA）, acetyl coenzyme A （acetyl-COA） and superoxide anion （02-） in heart tissue were measured. The signaling molecule of cardiac tissue and HO activity level were measured by Western blot. Results The level of glucose in group B was significantly higher than in group A （P 〈 0.01）, while the level of insulin （P 〈 0.01） and adiponectin （P 〈 0.05） in group B were lower than in group A. Isolated hearts from diabetic rats in Langendorff configuration displayed worse ventricular function and higher coronary resistance （CR） compared with hearts from control hearts, all the indexes had dramatically increased with the up-regulation of HO-1 on diabetic animals （P 〈 0.01）, while the level of CR had decreased （P 〈 0.01）. HO-1 inducer CoPP enhanced HO-1 protein levels and reduced oxidative stress in diabetic animals, which indicated by the decrease in heart 02. and MDA levels （P 〈 0.05）. HO-1 up-regulation increased signaling molecule level and reversed the eNOS/iNOS expression imbalance which was observed in the untreated diabetic heart （P 〈 0.05）. Moreover, after the improvement of HO-1 expression, a rise in malonyl-COA as well as a decrease in acetyl-COA was observed in diabetic hearts （P 〈 0.05）. Conclusion Up-regulation of heine oxygenase-1 can improve both cardiac function and coronary flow by blunting oxidative stress, restoring eNOS/

关 键 词：血红素氧合酶1 糖尿病 心脏重构 一氧化氮 冠脉循环 

分 类 号：R68[医药卫生—骨科学]