补中益气汤加减对糖尿病心肌病大鼠心功能及心肌细胞FABP3,PPARγ蛋白表达的影响
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摘要
目的:观察补中益气汤加减对2型糖尿病大鼠心功能及心型脂肪酸结合蛋白3(FABP3),过氧化物酶体增殖激活受体γ(PPARγ)蛋白的影响,探讨其保护2型糖尿病心肌病的作用机制。方法:6周高糖高脂饮食后,给予链脲佐菌素(STZ)腹腔注射(50 mg·kg-1)建立糖尿病大鼠模型,再按血糖随机分为正常组,模型组,补中益气汤加减组(21 g·kg-1),盐酸二甲双胍组(2 g·kg-1)。连续给药6周后通过超声心动图检测各组大鼠心脏结构及功能情况,结合所测血糖及血脂水平,判断为糖尿病心肌病大鼠造模成功。取大鼠心脏组织采用苏木素-伊红(HE)染色观察大鼠心肌形态;采用蛋白免疫印迹法(Western blot)检测大鼠心肌FABP3,PPARγ蛋白表达水平。结果:与正常组比较,模型组大鼠的空腹血糖,总胆固醇(TC),甘油三脂(TG),胰岛素(INS)水平均显著增高(P <0. 01),心率减慢,舒张期、收缩期左室内径(LVIDd)增加,收缩期左室后壁厚度降低,A峰E峰流速比值(E/A),短轴缩短率(FS),射血分数(EF)均显著降低(P <0. 01),FABP3蛋白表达均显著升高,PPARγ蛋白表达水平均显著降低(P <0. 01);与模型组比较,补中益气汤加减组大鼠空腹血糖,TC,TG,INS水平均显著降低(P <0. 01),心肌病变显著改善(P <0. 01),FABP3蛋白表达显著降低,PPARγ蛋白表达显著增加(P <0. 01)。结论:补中益气汤加减可改善糖尿病心肌病大鼠糖脂代谢紊乱,改善糖尿病心肌病大鼠心功能的作用,可增加心肌细胞的PPARγ表达,同时降低FABP3蛋白的表达。
Objective: To study the effects of modified Buzhong Yiqitang on cardiac function and fat acid binding protein3( FABP3) and peroxisome proliferator-activated receptor gamma( PPARγ) protein of cardiac myocytes in type 2 diabetic mellitus( T2 DM) rats,and to explore the mechanism of this prescription to protect T2 DM cardiomyopathy. Method: After 6 weeks of high-glucose and high-fat diet,streptozotocin( STZ) was intraperitoneally injected( 50 mg·kg-1) to establish a diabetic rat model,and then randomly divided into normal group,model group, modified Buzhong Yiqitang group( 21 g·kg-1) and metformin hydrochloride group( 2 g·kg-1). After continuous administration for 6 weeks,echocardiography was used to detect the cardiac structure and function of the rats in each group. Combined with the measured blood glucose level,it was judged that the rat model building of diabetic cardiomyopathy was successful. Rat heart tissue was dissected,and rat myocardial morphology was observed by hematoxylin-eosin( HE) staining. Western blot was used to detect the expression levels of FABP3 and PPARγ proteins in rat myocardium. Result: Compared with normal group,levels of blood sugar,total triglyceride( TC),triglyceride( TG), insulin( INS) in model group rats increased significantly( P < 0. 01),slow heart rate,diastolic and systolic left interior diameter( LVIDd) increases,the reduced systolic left ventricular posterior wall thickness,the ratio of peak A to peak E( E/A) ratio,short axial shortening rate( FS) and ejection fraction( EF) were different degree reduced( P < 0. 01),FABP3 protein expression were significantly elevated,PPARγ protein expression levels were significantly lower( P < 0. 01). Compared with model group,the situation of blood glucose,TC, TG, INS in modified Buzhong Yiqitang group was significantly improved( P < 0. 01),cardiomyopathy was significantly improved( P < 0. 01),FABP3 protein expression was significantly decreased,and PPARγ protein expression was significantly increased( P < 0. 01). Conclusion:Modified Buzhong Yiqitang can improve glucose and lipid metabolism disorder in diabetic cardiomyopathy rats,improve cardiac function in diabetic cardiomyopathy rats,increase the expression of PPARγ in cardiomyocytes,and reduce the expression of FABP3 protein.
Objective: To study the effects of modified Buzhong Yiqitang on cardiac function and fat acid binding protein3( FABP3) and peroxisome proliferator-activated receptor gamma( PPARγ) protein of cardiac myocytes in type 2 diabetic mellitus( T2 DM) rats,and to explore the mechanism of this prescription to protect T2 DM cardiomyopathy. Method: After 6 weeks of high-glucose and high-fat diet,streptozotocin( STZ) was intraperitoneally injected( 50 mg·kg-1) to establish a diabetic rat model,and then randomly divided into normal group,model group, modified Buzhong Yiqitang group( 21 g·kg-1) and metformin hydrochloride group( 2 g·kg-1). After continuous administration for 6 weeks,echocardiography was used to detect the cardiac structure and function of the rats in each group. Combined with the measured blood glucose level,it was judged that the rat model building of diabetic cardiomyopathy was successful. Rat heart tissue was dissected,and rat myocardial morphology was observed by hematoxylin-eosin( HE) staining. Western blot was used to detect the expression levels of FABP3 and PPARγ proteins in rat myocardium. Result: Compared with normal group,levels of blood sugar,total triglyceride( TC),triglyceride( TG), insulin( INS) in model group rats increased significantly( P < 0. 01),slow heart rate,diastolic and systolic left interior diameter( LVIDd) increases,the reduced systolic left ventricular posterior wall thickness,the ratio of peak A to peak E( E/A) ratio,short axial shortening rate( FS) and ejection fraction( EF) were different degree reduced( P < 0. 01),FABP3 protein expression were significantly elevated,PPARγ protein expression levels were significantly lower( P < 0. 01). Compared with model group,the situation of blood glucose,TC, TG, INS in modified Buzhong Yiqitang group was significantly improved( P < 0. 01),cardiomyopathy was significantly improved( P < 0. 01),FABP3 protein expression was significantly decreased,and PPARγ protein expression was significantly increased( P < 0. 01). Conclusion:Modified Buzhong Yiqitang can improve glucose and lipid metabolism disorder in diabetic cardiomyopathy rats,improve cardiac function in diabetic cardiomyopathy rats,increase the expression of PPARγ in cardiomyocytes,and reduce the expression of FABP3 protein.
引文
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[12]杨宇峰,秦延斌,石岩.益糖康干预糖调节受损的代谢综合征疗效评价[J].中国实验方剂学杂志,2014,20(22):197-199.
[13]陈红谨,石岩,杨宇峰,等.从血压分层的角度观察益糖康对痰热互结型并有IGR的代谢综合征患者的临床疗效[J].辽宁中医杂志,2012,39(11):2173-2175.
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[15]杨捷频.常规石蜡切片方法的改良[J].生物学杂志,2006(1):45-46.
[16]Loncarevic B,Trifunovic D,Soldatovic I,et al. Silent diabetic cardiomyopathy in everyday practice:a clinical and echocardiographic study[J]. BMC Cardiovasc Disord,2016,16(1):242.
[17]Gonzalo-Calvo D,Kenneweg F,Bang C,et al. Circulating long-noncoding RNAs as biomarkers of left ventricular diastolic function and remodelling in patients with wellcontrolled type 2 diabetes[J]. Sci Rep,2016,6:37354.
[18]Kirpichnikov D,Mc Farlane S I,Sowers J R. Metformin:an update[J]. Ann Intern Med,2002,137(1):25-33.
[19]How O J,Larsen T S,Hafstad A D,et al. Rosiglitazone treatment improves cardiac efficiency in hearts from diabetic mice[J]. Arch Physiol Biochem,2007,113(4/5):211-220.
[20]Owen M R,Doran E,Halestrap A P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain[J]. Biochem J,2000,348(3):607-614.
[21]ZHANG L,HE H,Balschi J A. Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration[J]. Am J Physiol Heart Circ Physiol,2007,293(1):457-466.
[22]Kim Y D,Park K G,Lee Y S,et al. Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP[J]. Diabetes,2008,57(2):306-314.
[23]Dubey P K,Goyal S,Mishra S K,et al. Identification of polymorphism in fatty acid binding protein 3(FABP3)gene and its association with milk fat traits in riverine buffalo(Bubalus bubalis)[J]. Trop Animal Health Prod,2016,48(4):849-853
[24]Baran A,C'widerska M,Bacharewicz-Szczerbicka J,et al. Serum fatty acid-binding protein 4 is increased in patients with psoriasis[J]. Lipids,2017,52(1):51-60.
[25]YAO D W,LUO J,HE Q Y,et al. Thyroid hormone responsive(THRSP)promotes the synthesis of mediumchain fatty acids in goat mammary epithelial cells[J]. J Dairy Sci,2016,99(4):3124-3133.
[26]程万里,王彦华,贾国洪. PPARα,PPARγ和胰岛素抵抗及糖尿病[J].邯郸医学高等专科学校学报,2005(4):120-122.
[2]Poornima I G, Parikh P, Shannon R P. Diabetic cardiomyopathy:the search for a unifying hypothesis[J]. Circ Res,2006,98(5):596-605.
[3]Factor S M,Borczuk A,Charron M J,et al. Myocardial alterations in diabetes and hypertension[J]. Diabetes Res Clin Pract,1996,Suppl 31:133-142.
[4]邓常青,熊曼琪.糖尿病性心肌病的发生机制及中医药防治研究进展[J].广州中医药大学学报,2001(2):181-184.
[5]Zimmerman A W,Veerkamp J H. New insights into the structure and function of fatty acid-binding proteins[J].Cell Mol Life Sci,2002,59(7):1096-1116
[6]Wolfgang Z,Appie H K,Eva S,et al. Histochemical localization of heart-type fatty-acid binding protein in human and murine tissues[J]. Histochemie,1995,103(2):147-156
[7]陈慧梅,陈惠萍.脂肪酸结合蛋白3的基础与临床[J].肾脏病与透析肾移植杂志,2011,20(1):62-66,71.
[8]LI Y,WANG P,ZHUANG Y,et al. Activation of AMPK by berberinepromotes adiponectin multimerization in3T3-L1 adipocytes[J]. FEBS Lett,2011,585(12):1735-1740.
[9]Marfella R, Portoghese M, Ferraraccio F,et al.Thiazolidinediones may contribute to the intramy-ocardial lipid accumulation in diabetic myocardium:effectson cardiac function[J]. Heart,2009, 95(12):1020-1022.
[10]张蓉芳,仝小林.仝小林教授应用补中益气汤精简方治疗糖尿病杂病经验[J].光明中医,2014,29(10):2180-2181.
[11]陈玉,王齐有,贺红梅.补中益气汤在糖尿病及其并发症领域的应用心得[J].成都中医药大学学报,2016,39(1):71,95.
[12]杨宇峰,秦延斌,石岩.益糖康干预糖调节受损的代谢综合征疗效评价[J].中国实验方剂学杂志,2014,20(22):197-199.
[13]陈红谨,石岩,杨宇峰,等.从血压分层的角度观察益糖康对痰热互结型并有IGR的代谢综合征患者的临床疗效[J].辽宁中医杂志,2012,39(11):2173-2175.
[14]陈奇.中药药理研究方法学[M].北京:人民卫生出版社,1993:33.
[15]杨捷频.常规石蜡切片方法的改良[J].生物学杂志,2006(1):45-46.
[16]Loncarevic B,Trifunovic D,Soldatovic I,et al. Silent diabetic cardiomyopathy in everyday practice:a clinical and echocardiographic study[J]. BMC Cardiovasc Disord,2016,16(1):242.
[17]Gonzalo-Calvo D,Kenneweg F,Bang C,et al. Circulating long-noncoding RNAs as biomarkers of left ventricular diastolic function and remodelling in patients with wellcontrolled type 2 diabetes[J]. Sci Rep,2016,6:37354.
[18]Kirpichnikov D,Mc Farlane S I,Sowers J R. Metformin:an update[J]. Ann Intern Med,2002,137(1):25-33.
[19]How O J,Larsen T S,Hafstad A D,et al. Rosiglitazone treatment improves cardiac efficiency in hearts from diabetic mice[J]. Arch Physiol Biochem,2007,113(4/5):211-220.
[20]Owen M R,Doran E,Halestrap A P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain[J]. Biochem J,2000,348(3):607-614.
[21]ZHANG L,HE H,Balschi J A. Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration[J]. Am J Physiol Heart Circ Physiol,2007,293(1):457-466.
[22]Kim Y D,Park K G,Lee Y S,et al. Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP[J]. Diabetes,2008,57(2):306-314.
[23]Dubey P K,Goyal S,Mishra S K,et al. Identification of polymorphism in fatty acid binding protein 3(FABP3)gene and its association with milk fat traits in riverine buffalo(Bubalus bubalis)[J]. Trop Animal Health Prod,2016,48(4):849-853
[24]Baran A,C'widerska M,Bacharewicz-Szczerbicka J,et al. Serum fatty acid-binding protein 4 is increased in patients with psoriasis[J]. Lipids,2017,52(1):51-60.
[25]YAO D W,LUO J,HE Q Y,et al. Thyroid hormone responsive(THRSP)promotes the synthesis of mediumchain fatty acids in goat mammary epithelial cells[J]. J Dairy Sci,2016,99(4):3124-3133.
[26]程万里,王彦华,贾国洪. PPARα,PPARγ和胰岛素抵抗及糖尿病[J].邯郸医学高等专科学校学报,2005(4):120-122.
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