脂联素对体外循环心肌胰岛素抵抗模型犬心肌腺苷酸活化蛋白激酶表达的影响
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摘要
目的:探讨脂联素(APN)对体外循环(CPB)心肌胰岛素抵抗(IR)模型犬心肌腺苷酸活化蛋白激酶(AMPK)表达的影响。方法:将24只犬随机分为对照组、模型组、APN组(36μg/kg)、AMPK抑制剂组(APN 36μg/kg+AMPK抑制剂复合制剂C 0.5mg/kg),每组6只。所有犬行CPB术,除对照组不给药外,其余各组犬建立CPB心肌IR模型,并于主动脉夹闭后灌注不含药或含相应药物的St.Thomas心脏停搏液。分别在CPB转流前和心缺血60 min后再灌注15、90 min收集冠状静脉窦血、颈动脉血,取左心室心尖部组织,测定并计算心肌葡萄糖摄取率和胰岛素抵抗指数(IRI),监测心肌损伤指标[肌钙蛋白T(c TnT)浓度]和心功能指标[左室收缩压(LVSP)、左室内压最大上升速率(+dp/dt_(max))]变化,检测磷酸化AMPK(p-AMPK)水平。结果:转流前各组犬之间上述指标差异均无统计学意义(P>0.05)。与对照组比较,模型组犬再灌注15、90 min的心肌葡萄糖摄取率、LVSP、+dp/dt_(max)和pAMPK水平均明显降低(P<0.05),IRI和cTnT浓度均明显升高(P<0.05)。与模型组比较,APN组和AMPK抑制剂组犬再灌注15、90 min的心肌葡萄糖摄取率、LVSP、+dp/dt_(max)和p-AMPK水平均明显升高(P<0.05),IRI和cTnT浓度均明显降低(P<0.05),且APN组效果强于AMPK抑制剂组(P<0.05)。结论:APN可促进心肌对葡萄糖的摄取及代谢以助心功能恢复,其可能是通过增强AMPK活性来发挥效应的。
OBJECTIVE: To investigate the effects of adiponectin(APN) on the expression of myocardial AMPK in myocardial insulin resistance(IR)model dogs during cardiopulmonary bypass(CPB). METHODS:Totally 24 dogs were randomly divided into control group,model group,APN group(36 μg/kg),AMPK inhibition group(APN 36 μg/kg + AMPK inhibitor compound C 0.5 mg/kg),with 6 dogs in each group. All dogs underwent CPB;except for control group without medicine,CPB myocardial IR model were established in other groups,and perfused with St.Thomas cardiac cardioplegia lipid no medicine or containing relevant drugs after main artery block. Coronary sinus blood and carotid artery blood samples were collected before bypass and after 15,90 min reperfusion following 60 min myocardial ischemia. Left ventricular apical tissue was taken,and the uptake rate of myocardial glucose and insulin resistance index(IRI) were determined and calculated;the changes of myocardial injury indexes(cTnT concentration)and cardiac function indexes(LVSP,+dp/dt_(max))were monitored. The level of p-AMPK was detected. RESULTS:There was no statistical significance in above indexes of dogs before bypass(P>0.05). Compared with control group,the rate of myocardial glucose uptake,the levels of LVSP,+dp/dt_(max)and p-AMPK in model group were decreased significantly after 15,90 min reperfusion(P<0.05),and the concentrations of IRI and cTnT were increased significantly(P<0.05). Compared with model group,the rate of myocardial glucose uptake,LVSP,+ dp/dt_(max)and p-AMPK were increased significantly in APN group and AMPK inhibitor group(P<0.05),while the concentrations of IRI and cTnT were decreased significantly(P<0.05); moreover, the effect of APN group was better than that of AMPK inhibitor group(P<0.05).CONCLUSIONS:APN can promote myocardial glucose uptake and metabolism,and contribute the recovery of cardiac function,the mechanism of which may be associated with increasing the activity of AMPK.
OBJECTIVE: To investigate the effects of adiponectin(APN) on the expression of myocardial AMPK in myocardial insulin resistance(IR)model dogs during cardiopulmonary bypass(CPB). METHODS:Totally 24 dogs were randomly divided into control group,model group,APN group(36 μg/kg),AMPK inhibition group(APN 36 μg/kg + AMPK inhibitor compound C 0.5 mg/kg),with 6 dogs in each group. All dogs underwent CPB;except for control group without medicine,CPB myocardial IR model were established in other groups,and perfused with St.Thomas cardiac cardioplegia lipid no medicine or containing relevant drugs after main artery block. Coronary sinus blood and carotid artery blood samples were collected before bypass and after 15,90 min reperfusion following 60 min myocardial ischemia. Left ventricular apical tissue was taken,and the uptake rate of myocardial glucose and insulin resistance index(IRI) were determined and calculated;the changes of myocardial injury indexes(cTnT concentration)and cardiac function indexes(LVSP,+dp/dt_(max))were monitored. The level of p-AMPK was detected. RESULTS:There was no statistical significance in above indexes of dogs before bypass(P>0.05). Compared with control group,the rate of myocardial glucose uptake,the levels of LVSP,+dp/dt_(max)and p-AMPK in model group were decreased significantly after 15,90 min reperfusion(P<0.05),and the concentrations of IRI and cTnT were increased significantly(P<0.05). Compared with model group,the rate of myocardial glucose uptake,LVSP,+ dp/dt_(max)and p-AMPK were increased significantly in APN group and AMPK inhibitor group(P<0.05),while the concentrations of IRI and cTnT were decreased significantly(P<0.05); moreover, the effect of APN group was better than that of AMPK inhibitor group(P<0.05).CONCLUSIONS:APN can promote myocardial glucose uptake and metabolism,and contribute the recovery of cardiac function,the mechanism of which may be associated with increasing the activity of AMPK.
引文
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[13] LAWRENCE H,VLAD G. AMP-activated protein kinase regulation and biological actions in the heart[J]. Circ Res,2012,111(6):800–814.
[14] PAIVA MA. Transitory activation of AMPK at reperfusion protects the ischaemic-reperfused rat myocardium against infarction[J]. Cardiovasc Drugs Ther,2010,24(1):25–32.
[15]王峰,梁贵友,刘达兴,等.盲视插管测定犬冠状静脉窦血流量的方法[J].中华实验外科杂志,2015,32(5):1065.
[16] FERRANNINI E,SANTORO D,BONADONNA R,et al.Metabolic and hemodynamic effects of insulin on human hearts[J]. Am J Physiol,1993,264(2):E308–E315.
[17] KATZ A,NAMBI SS,MATHER K,et al. Quantitative insulin sensitivity check index:a simple,accurate method for assessing insulin sensitivity in humans[J]. Clin Endocrinal Metab,2000,85(7):2402–2410.
[18] FRYER LG,CARLING D. AMP-activated protein kinase and the metabolic syndrome[J]. Biochem Soc Trans,2005,33(2):362–366.
[19] MISRA P,CHAKRABARTI R. The role of AMP kinase in diabetes[J]. Indian J Med Res,2007,125(3):389–398.
[20]张登沈,梁贵友,刘达兴,等.阿卡地新对体外循环心肌缺血再灌注损伤模型犬心肌能量代谢的影响[J].中国药房,2017,28(28):3918–3923.
[21] MIRMIRAN P,HOSSEINI S,HOSSEINPOUR-NIAZI S,et al. Legume consumption increase adiponectin concentrations among type 2 diabetic patients:a randomized crossover clinical trial[J]. Endocrinol Diabetes Nutr,2019,66(1):49–55.
[22] WICKS SE,VANDANMAGSAR B,HAYNIE KR,et al.Mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism[J]. Proc Natl Acad Sci USA,2015,112(25):E3300–E3309.
[2] WANG F,LIANG GY,LIU DX,et al. Effect of Si-RNAsilenced HIF-1αgene on myocardial ischemia-reperfusion-induced insulin resistance[J]. In J Clin Exp Med,2015,8(9):15514–15520.
[3]梁贵友,宋宣统,蔡庆勇,等. BQ123对体外循环缺血再灌注心肌胰岛素抵抗干预作用的实验研究[J].中国药房,2008,19(28):2179–2181.
[4] LIU B,LIANG GY,XU G,at al. Intervention of rosiglitazone on myocardium Glut-4 mRNA expression during ischemia-reperfusion injury in cardiopulmonary bypass in dogs[J]. Mol Cell Biochem,2013,373(1):279–284.
[5] FANG H,JUDD RL. Adiponectin regulation and function[J]. Compr Physiol,2018,8(3):1031–1063.
[6] BOURSEREAU R,ABOU-SAMRA M,LECOMPTE S,et al. New targets to alleviate skeletal muscle inflammation:role of microRNAs regulated by adiponectin[J]. Sci Rep,2017.DOI:10.1038/srep43437.
[7] XU W,TIAN M,ZHOU Y. The relationship between insulin resistance,adiponectin and C-reactive protein and vascular endothelial injury in diabetic patients with coronary heart disease[J]. Exp Ther Med,2018,16(3):2022–2026.
[8] LECOMPTE S,ABOU-SAMRA M,BOURSEREAU R,et al. Skeletal muscle secretome in duchenne muscular dystrophy:a pivotal anti-inflammatory role of adiponectin[J]. Cell Mol Life Sci,2017,74(13):2487–2501.
[9] FANTUZZI G. Adiponectin in inflammatory and immunemediated diseases[J]. Cytokine,2013,64(1):1–10.
[10] SAYEED M,GAUTAM S,VERMA DP,et al. A collagen domain-derived short adiponectin peptide activates APPL1 and AMPK signaling pathways and improves glucose and fatty acid metabolisms[J]. J Biol Chem,2018,293(35):13509–13523
[11] CHANG E,CHOI JM,PARK SE,et al. Adiponectin deletion impairs insulin signaling in insulin-sensitive but not insulin-resistant 3T3-L1 adipocytes[J]. Life Sci,2015,132(1):93–100.
[12]汪俊,邵名亮,曹蘅,等.脂联素对大鼠心肌缺血再灌注损伤的保护作用[J].中华心血管病杂志,2010,38(3):252–258.
[13] LAWRENCE H,VLAD G. AMP-activated protein kinase regulation and biological actions in the heart[J]. Circ Res,2012,111(6):800–814.
[14] PAIVA MA. Transitory activation of AMPK at reperfusion protects the ischaemic-reperfused rat myocardium against infarction[J]. Cardiovasc Drugs Ther,2010,24(1):25–32.
[15]王峰,梁贵友,刘达兴,等.盲视插管测定犬冠状静脉窦血流量的方法[J].中华实验外科杂志,2015,32(5):1065.
[16] FERRANNINI E,SANTORO D,BONADONNA R,et al.Metabolic and hemodynamic effects of insulin on human hearts[J]. Am J Physiol,1993,264(2):E308–E315.
[17] KATZ A,NAMBI SS,MATHER K,et al. Quantitative insulin sensitivity check index:a simple,accurate method for assessing insulin sensitivity in humans[J]. Clin Endocrinal Metab,2000,85(7):2402–2410.
[18] FRYER LG,CARLING D. AMP-activated protein kinase and the metabolic syndrome[J]. Biochem Soc Trans,2005,33(2):362–366.
[19] MISRA P,CHAKRABARTI R. The role of AMP kinase in diabetes[J]. Indian J Med Res,2007,125(3):389–398.
[20]张登沈,梁贵友,刘达兴,等.阿卡地新对体外循环心肌缺血再灌注损伤模型犬心肌能量代谢的影响[J].中国药房,2017,28(28):3918–3923.
[21] MIRMIRAN P,HOSSEINI S,HOSSEINPOUR-NIAZI S,et al. Legume consumption increase adiponectin concentrations among type 2 diabetic patients:a randomized crossover clinical trial[J]. Endocrinol Diabetes Nutr,2019,66(1):49–55.
[22] WICKS SE,VANDANMAGSAR B,HAYNIE KR,et al.Mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism[J]. Proc Natl Acad Sci USA,2015,112(25):E3300–E3309.