通络方剂和抗氧化剂对大鼠糖尿病心肌病变的保护作用及其机制研究
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摘要
目的:研究通络方剂和褪黑素、α-硫辛酸和金属硫蛋白等抗氧化剂对糖尿病大鼠心肌细胞和组织的抗凋亡作用及超氧化物歧化酶2(SOD2)、泛素D表达的影响及其作用机理。方法:乳鼠心肌细胞在高糖培养基(25mmo/L)中培养48h,MTT法检测细胞活力,RT-PCR检测SOD2mRNA表达;链脲佐菌素诱导大鼠糖尿病模型,电镜观察心肌组织形态,免疫组化原位检测细胞凋亡,基因芯片技术比较大鼠心肌组织中基因表达差异,RT-PCR检测泛素DmRNA表达。结果:α-硫辛酸可增强高糖培养的心肌细胞SOD2mRNA表达,金属硫蛋白、通络方剂和大剂量褪黑素减少心肌细胞凋亡,物质代谢相关基因和细胞骨架相关基因在糖尿病大鼠心肌组织明显下调,通络方剂和大剂量褪黑素可使上述基因上调。结论:褪黑素、α-硫辛酸和金属硫蛋白等抗氧化剂通过抑制氧化应激反应,抑制凋亡,对糖尿病大鼠心肌起保护作用,通络方剂对糖尿病心肌病变也有一定保护作用。
Objective: to investigate the effect of Tongluo recipe and melatonin, Metallothionein, a-lipoic acid on diabetic cardiomyopathy in rats. Method: myocardial cell were cultured in high glucose (25mmol/L) for 48h, SODmRNA were measured by RT-PCR; Rats were induced in diabetes with injection of Streptozocin, histological changes of hearts were determined by electron microscope; the difference of rats heart’s gene were determined with DNA microarray, UbDmRNA were measured by RT-PCR. Result : a-lipoic acid increase the expression of SODmRNA in rat myocardial cell, Tongluo recipe, melatonin and Metallothionein decrease the apoptosis of myocardium, energy metabolism related gene were down regulated in diabetic rat’s myocardium, melatonin up regulated the gene expression mentioned above. Conclusion: oxidative stress plays an important role in the pathogenesis of diabetic cardiomyopathy. Melatonin, Metallothionein and a-lipoic acid have protective effect on diabetic rat’s myocardium.
Objective: to investigate the effect of Tongluo recipe and melatonin, Metallothionein, a-lipoic acid on diabetic cardiomyopathy in rats. Method: myocardial cell were cultured in high glucose (25mmol/L) for 48h, SODmRNA were measured by RT-PCR; Rats were induced in diabetes with injection of Streptozocin, histological changes of hearts were determined by electron microscope; the difference of rats heart’s gene were determined with DNA microarray, UbDmRNA were measured by RT-PCR. Result : a-lipoic acid increase the expression of SODmRNA in rat myocardial cell, Tongluo recipe, melatonin and Metallothionein decrease the apoptosis of myocardium, energy metabolism related gene were down regulated in diabetic rat’s myocardium, melatonin up regulated the gene expression mentioned above. Conclusion: oxidative stress plays an important role in the pathogenesis of diabetic cardiomyopathy. Melatonin, Metallothionein and a-lipoic acid have protective effect on diabetic rat’s myocardium.
引文
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[1]Way KJ,Isshiki K,Suzuma K,et a1.Expression of connective tissue growth factor is increased in injured myocardium associated with proteinkinase C beta2 activation and diabetes.Diabetes. 2002; 51(9): 2709-18.
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[15] Couture R, Girolami JP. Putative roles of kinin receptors in the therapeutic effects of angiotensin 1-converting enzyme inhibitors in diabetes mellitus. Eur J Pharmacol 2004;500(1-3):467-85
[2] Park S, Sohn S, Kineman R D. Fasting-induced changes in the hypothalamic -pituitary-GH axis in the absence of GH expression: lessons from the spontaneous dwarf rat. J Endocrinol, 2004, 180:369-78.
[3] Colombrita C, Calabrese V, Stella AMG, et al. Regional rat brain distribution of Superoxide dismutase mRNA: relevance of redox homeostasis in the aging processes. Exp Biol Med, 2003, 228: 517-24.
[4] Harary L,Farley B. In vitro studies of single isolated beating heart cells. Science. 1960, 131: 1674-75.
[5]Yamamoto K, Ohki R, Lee R T, et a1. Peroxisome proliferator-activated receptor activators inhibit cardiac hypertrophy in cardiac myocytes. Circulation, 2001, 104: 1670-81.
[6] Fuller SJ, Davies EL, Gillespie BJ, et a1. Mitogen-activated protein kinase phosphataseⅠinhibits the stimulation of expression by hypertrophic agonists in cardiac myocytes. Biochem, 1997, 323(Pt 2):313-9.
[7] Pinsky D J, Aji W, Szabolcs M, et a1.Nitric oxide triggers programmed cell death (apoptosis) of adult rat ventricular myocytes in culture.Am J PhysioI, 1999,277(3 Pt 2): H1189-99.
[8] Yonemochi H, Yasunaga S, Teshima Y, et al. Mechanism of adrenergic receptor up regulation induced by ACE inhibition in cultured neonatal rat cardiac myocytes. Circ, 1998, 97: 2268-73
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[10] 刘斌.细胞培养中的研究方法.见:司徒镇强主编.细胞培养.西安:世界图书出版公司,2004,250-252.
[11] Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54(6):1615-25.
[12] 周庆峰,王洪新,王桂君,等.高糖对去甲肾上腺素诱导的心肌细胞肥大的促进作用.中国药理学通报,2003,19(9):1054-7.
[13]Yokota T, Ma RC, Park JY, et al. Role of protein kinase C on the expression of platelet-derived growth factor and endothelin-1 in the retina of diabetic rats and cultured retinal capillary pericytes. Diabetes. 2003 ; 52 3):838-45.
[14] Sung MJ, Kim W, Ahn SY, et al. Protective effect of alpha-lipoic acid in lipopolysaccharide -induced endothelial fractalkine expression. Circ Res. 2005, 7:880-90.
[15] Bojunga J, Nowak D, Mitron PS, et al. Antioxidative treatment prevents activation of death-receptor- and mitochondrion-dependent apoptosis in the hearts of diabetic rats. Diabetologia. 2004 , 47:2072-80.
[16] Stockklauser-Farber K, Ballhausen T, Laufer A, et al. Influence of diabetes on cardiac nitric oxide synthase expression and activity. Biochim Biophys Acta. 2000, 1535: 10-20.
[17] Ramnath S, Tritschler HJ, Eckel J. Stimulation of cardiac glucose transport by thioctic acid and insulin. Horm Metab Res. 1999,31:632-5.
[18] Strodter D, Lehmann E, Lehmann U, et al. The influence of thioctic acid on metabolism and function of the diabetic heart. Diabetes Res Clin Pract. 1995, 29: 19-26.
[19] Xie JT, Shao ZH, Vanden Hoek TL. Antioxidant effects of ginsenoside Re in cardiomyocytes. Eur J Pharmacol, 2006, 532:201-7.
[20] Cho WC, Chung WS, Lee SK, et al. Ginsenoside Re of Panax ginseng possesses significant antioxidant and antihyperlipidemic efficacies in streptozotocin-induced diabetic rats. Eur J Pharmacol, 2006, 550:173-9.
[21] Kang KS, Kim HY, Pyo JS, et al. Increase in the free radical scavenging activity of ginseng by heat-processing. Biol Pharm Bul,. 2006, 29:750-4.
[22]Shao ZH, Xie JT, Vanden Hoek TL. Antioxidant effects of American ginseng berry extract in cardiomyocytes exposed to acute oxidant stress. Biochim Biophys Acta. 2004, 1670:165-71.
[23] Liao B, Newmark H, Zhou R. Neuroprotective effects of ginseng total saponinand ginsenosides Rb1 and Rg1 on spinal cord neurons in vitro. Exp Neurol. 2002, 173: 224-34.
[24] Clark W A, Decker M L, Behnke-Barclay M, et a1. Cell contact as an independent factor modulating cardiacmyocytes hypertrophy and survival in long term primary culture. J Mol Cell Cardiol, 1998, 30(1):139-55.
[1] Hamby RI,Zoneraich S, Sherman L.Diabetic cardiomyopathy.JAMA,1974; 229(13): 1749-54.
[2] Schannwell CM, Schneppenheim M,Perings S,et a1.Left ventricular diastolic dysfunction as an early manifestation of diabetic cardiomyopathy.Cardiology,2002;98(1-2):33-9.
[3] Poirier P,Bogaty P,Garneau C,et a1.Diastolic dysfunction in normotensive men with well—controlled type 2 diabetes:importance of maneuvers in echocardiographic screening for preclinical diabetic cardiomyopathy.Diabetes Care,2001,24(1):5-10.
[4] 白永虹,田杰,江德勤,等. 大鼠心肌病模型的建立及彩色超声心动图监测的研究. 重庆医学,2005,34(2):168-70
[5] Fiordaliso F, Li B, Latini R, et a1.Myocyte death in streptozotocin -induced diabetes in rats in angiotensin II- dependent. Lab Invest 2000; 80(4): 513-27
[6]Rodrique B, Cam MC, Mcneill JH. Metabolic disturbances in diabetic cardiomyopathy. Mol Cell Biochem 1998;180(1):53-7
[7] Kockx MM,Knaapen MW.The role of apoptosis in vascular disease.J Pathol,2000,190:267-80.
[8] Hengartner M.The biochemistry of apoptosis.Nature,2000,407:770 -76.
[9] Cai L, Li W, Wang GW, et al. Hyperglycemia induced apoptosis in mouse myocardium. Diabetes,2002,51:1938-48
[10]张超英,党寅虎,王 辉,等.硒缺乏对大鼠心肌细胞凋亡的影响及褪黑素的干预作用. 西安交通大学学报(医学版),2004,25(6):542-44
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