小檗碱治疗实验性糖尿病心肌病作用和机制研究
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摘要
第一部分实验性2型糖尿病心肌病大鼠模型建立与评价
目的：建立和评价实验性2型糖尿病心肌病(DC)大鼠模型,探究高糖脂饮食在模型诱导过程中的作用。方法：将雄性Wistar大鼠随机分成正常对照组(Control),高糖脂饮食组(HSF)和高糖脂饮食负荷小剂量链脲佐菌素组(HSF-STZ).Control大鼠喂养常规饲料12周,HSF大鼠喂饲高糖高脂饲料12周,HSF-STZ大鼠喂饲高糖高脂饲料6周后一次性腹腔注射30 mg/kg STZ并继续给予高糖高脂饲料6周以诱导2型糖尿病心肌病病变。监测大鼠一般状态；容积阻抗法测定心排量；左心室插管测定血流动力学指标；称重法测定大鼠心脏重量,计算心重指数(HW/BW)和左心室肥厚指数(LVW/BW):心脏赤道面横切作常规HE染色,观察病理变化并计算左心室前壁(LVWT)和室间隔厚度(IST)；生化法测定血液糖、脂代谢指标和心肌组织胶原含量。结果：①HSF-STZ大鼠腹腔注射STZ并继续喂养6周后,与正常大鼠比较,进食量和饮水量分别显著增加16%和84%。②与Control大鼠比较,HSF大鼠喂养高糖高脂饲料4周后,总胆固醇(TCH,26%)和甘油三脂(TG,34%)水平显著升高；HSF-STZ大鼠腹腔注射STZ并继续喂养6周后血浆TCH(44%)、血浆游离脂肪酸(NEFA,100%)和心肌组织NEFA(69%)水平显著升高,高密度脂蛋白值(HDL)降低26%；同时血浆空腹血糖(FBG,233%)、糖化血红蛋白(HbAlc,35%)和糖化血清蛋白(GSP,28%)明显增加。③与Control大鼠比较,HSF-STZ大鼠左心室收缩压(LVSP,15%)、每搏输出量(SV,26%)和心排量(CO,23%)显著降低,左心室舒张末期压力(LVEDP,44%)和左心室最大舒张速率(一dp/dtmax,29%)明显升高。④与Control大鼠比较,HSF-STZ大鼠HW/BW和LVW/BW指数分别升高15%和10%。⑤HE染色结果显示HSF-STZ大鼠心肌纤维排列紊乱、断裂,心肌细胞肥大,细胞核边缘不清、融合,甚至消失；LVWT(33%).IST值(80%)和胶原含量(18%)显著增加。结论：①Wistar大鼠高糖高脂饲料喂养负荷链脲佐菌素(30 mg/kg)腹腔注射可建立实验性2型糖尿病心肌病大鼠模型。②高糖高脂饲料喂养可诱导肥胖和高血脂,在2型糖尿病心肌病大鼠模型发病过程中有重要作用。
第二部分小檗碱治疗2型糖尿病心肌病作用及机制整体实验研究
目的：建立实验性2型糖尿病心肌病大鼠模型,观察小檗碱对模型大鼠机体一般状况,血糖、血脂和心脏功能和结构,心肌组织NEFA、脂肪酸转运和氧化酶含量,以及心肌组织过氧化物增殖体激活受体(PPAR)α、PPARγ和葡萄糖转运体4 (GLUT4) mRNA基因和蛋白表达的影响。方法：糖尿病心朋病大鼠模型(DC rat model)建立同第一部分,小檗碱(Berberine)分为7.5、15和30 mg/kg组,阳性药包括二甲双胍(Metformin) 140 mg/kg组、罗格列酮(Rosiglitazone) 2 mg/kg组和卡托普利(Captopril) 45 mg/kg组,另设正常对照组(Control)。治疗组动物从注射STZ后72小时按相应剂量开始灌胃给药6周。定期监测各组大鼠一般体征变化；生化法检测血糖和血脂,以及心朋组织胶原(Collagen)、肌酸激酶(CK)和NEFA含量；容积阻抗法测定心排量,左心室插管测定血流动力学指标；称重法测定大鼠心脏重量,计算HW/BW和LVW/BW;心脏作常规HE染色,计算LVWT和IST; Elisa去检测心肌红织脂肪酸转运蛋白-1(FATP-1)、脂肪酸转运蛋白(FATPs)和脂肪酸β氧化酶(FA-β-oxidase)含量。实时定量PCR检测心肌组织PPARα、PPARγ和GLUT mRNA基因表达；Western blot去检测PPAR a、PPAR 7和GLUT4蛋白表达。结果：①Berberine 30 mg/kg和Metformin 140 mg/kg可显著抑制DC rat mode体重降低；Metformin 140 mg/kg降低模型大鼠饮水量10%,其余药物均未明显改变动物模型的饮食量。②与DC rat model比较,小檗碱30 mg/kg和Metformi 140 mg/kg可显著降低FBG(69%和67%)、GSP(40%和34%)、HbAlc(46%和42%)和果糖胺(FMN)(40%和34%)含量；Rosiglitazone 2 mg/kg可显著降低降低FBG(36%)和HbAl。(24%)；Captopril 45 mg/kg可明显降低HbAl(31%)。③与DC rat model比较,Berberine 30 mg/kg组动物TCH(42%)、TG(42%)和低密度脂蛋白(LDL)值(40%)显著降低；Rosiglitazone 2 mg/k可显著降低TG(49%)和LDL(37%)水平；Metformin显著降低TG值达41%④与DC rat model比较,小檗碱30 mg/kg组动物LVSP (14%)和左心室最夕收缩速率(+dp/dtmax,81%)明显增加,LVEDP (80%)和-dp/dtmax (55%)显著降低,心排量增加60%; Captopril 45 mg/kg组LVSP(15%)和+dp/dtmax(77%显著增加,-dp/dtmax降低52%,心排量增加54%；Metformin 140 mg/kg组动物+dp/dtmax上升60%,心排量增加71%。⑤与DC大鼠模型比较,小檗碱30 mg/k治疗可明显降低HW/BW (6%)和LVW/BW (9%)指数、心肌组织胶原含量(32%)、IST(20%)和LVWT (46%)值；Metformin 140 mg/kg显著降低术型大鼠心肌胶原含量(26%)和IST水平(26%)。⑥光镜下观察左心室纵切片HE染色结果显示,Berberine 30 mg/kg.Metformin 140 mg/kg和Captopril 45 mg/kg治疗后,心肌组织病理损伤有明显的改善,心肌细胞排列较规则,细胞核清晰可见。⑦与正常大鼠比较,DC rat model心肌组织NEFA和CK含量分别显著升高69%和95%；与DC rat model比较,小檗碱7.5、15和30 mg/kg组动物心肌NEFA含量分别降低34%、27%和25%,阳性药Metformin 140 mg/kg(36%)和Captopril 45 mg/kg(24%)组动物心肌组织NEFA含量也显著下降；Berberine 30 mg/kg.Metformin.Rosiglitazone和Captopril组动物心肌组织CK水平分别降低20%、39%、26%和18%；另外,DC rat model心肌组织FATP一1 (68%).FATPs(22%)和FA-p-Oxidase(47%)含量较正常大鼠比较显著降低,小檗碱30 mg/kg治疗后,大鼠心肌组织FATP-1、FATPs和FA-β-oxidase含量分别提高了159%、56%和91%。⑧与正常大鼠比较,DC rat model心肌组织PPARαmRNA表达升高了80%,Berberine 30mg/kg(54%).Metformin 140mg/kg(40%).Rosiglitazone 2 mg/kg(47%)及Captopril 45 mg/kg(38%)可显著下调心肌组织的PPARαmRNA表达。⑨与正常大鼠比较,DC rat model心肌组织PPARγmRNA基因(38%)和蛋白(40%)表达明显降低；Berberine 30 mg/kg组动物PPARγ基因(50%)和蛋白(83%)表达与大鼠模型比较显著升高；同时,DC rat model心肌组织GLUT4 mRNA基因(34%)和蛋白(68%)表达明显比正常大鼠降低；与DC rat model比较,Berberine 30 mg/kg(32%)和Captopril 45 mg/kg(36%)组动物GLUT4 mRNA基因表达明显升高,另外Berberine 30 mg/kg(133%).Metformin 140 mg/kg(208%)和Rosiglitazone 2 mg/kg(166%)组动物GLUT4蛋白表达也显著升高。结论：小檗碱可显著改善高糖高脂负荷小剂量STZ诱导的实验性2型糖尿病心肌病大鼠模型心脏舒张功能和收缩功能损伤,并且抑制心肌胶原积聚和左心室重构；同时还可以显著降低大鼠模型血糖、血脂各项指标,并且对糖尿病大鼠一般体征状态有明显改善作用；其作用机制可能与提高心肌组织转录调控因子PPARγ和GLUT4 mRNA基因和蛋白表达,降低PPARαmRNA基因表达,上调下游目的因子FATP-1、FATPs和FA-β-oxidase含量,改善心肌组织脂肪酸的转运氧化能力,提高葡萄糖的转运能力,抑制心肌组织脂质积聚有关。
第三部分小檗碱对3T3-L1前脂肪细胞分化、脂肪积聚和脂肪因子分泌的影响
目的：培养小鼠3T3-L1前脂肪细胞,观察小檗碱对前脂肪细胞向脂肪细胞分化、细胞甘油三脂积聚以及脂肪因子基因表达的影响。方法：培养小鼠3T3-L1细胞,用含10%胎牛血清(FBS)、100U/mL青霉素、100μg/mL链霉素、5μg/mL胰岛素、1μM地塞米松和500μM 3-异丁基-1-甲基黄嘌呤的高糖DMEM培养基诱导分化(Day 0),为期3天(Day 0-Day 2).细胞于Day 3,Day 5和Day 7用小檗碱(5μM、10μM和20μM)处理,共给药3次,Day 8进入实验。未分化的细胞称为前脂肪细胞(Preadipocyte)。油红-O染色测定细胞内脂滴积聚,观察细胞内脂滴大小。生化法测定细胞内蛋白和甘油三脂含量。逆转录聚合酶链反应法(RT-PCR)检测调控前脂肪细胞分化基因和脂质代谢相关基因CCAAT/增强子结合蛋白(C/EBP)α、C/EBPβ、PPARγ、脂肪细胞脂质结合蛋白(aP2)和脂肪酸合成酶(FAS),以及脂肪因子脂联素(adiponectin)、瘦素(leptin)、抵抗素(resistin)、血管紧张素原(AGT)、纤溶酶原激活物抑制剂-1(PAI-1)和单核巨噬细胞趋化蛋白-1(MCP-1)基因表达。结果：①小檗碱(5、10和20μM)呈剂量依赖性分别降低脂肪细胞TG值26%、37%和43%,抑制脂质积聚。②小檗碱10μM和20μM可降低脂肪细胞C/EBP a(21%和47%)和PPAR y mRNA(21%和55%)基因表达；小檗碱20μM显著降低C/EBPβmRNA基因表达16%。③小檗碱10μM和20μM分别降低aP2基因18%和40%；20μM显著降低FAS基因表达18%。④前脂肪细胞中未见adiponectin. leptin和resistin基因表达,而脂肪细胞中adiponectin、leptin和resistin mRNA表达明显升高(P<0.001),小檗碱5μM、10μM和20μM呈剂量依赖性分别降低adiponectin(9%、46%和85%)、leptin(33%、75%和100%)和resistin(13%、63%和82%)在脂肪细胞中的表达。⑤3T3-L1前脂肪细胞分化为脂肪细胞后,细胞内AGT mRNA基因表达明显升高84%,小檗碱10μM和20μM分别降低脂肪细胞中AGT mRNA表达15%和24%。⑥3T3-L1前脂肪细胞与脂肪细胞均可以分泌PAI-1和MCP-1,且二者比较,PAI-1和MCP-1 mRNA基因表达并没有明显的差异；小檗碱20μM明显降低脂肪细胞内PAI-1(12%)和MCP-1 mRNA (28%)基因表达。结论：小檗碱可抑制3T3-L1前脂肪细胞向脂肪细胞分化,降低细胞内TG含量和脂滴积聚,这与其抑制细胞分化过程中转录因子C/EBPβ、C/EBP a和PPAR y以及下游与脂肪代谢调节相关的基因aP2和FAS基因表达有关。小檗碱可下调脂肪因子adiponectin、leptin、resistin、AGT、PAI-1和MCP-1基因表达,进一步证实小檗碱对肥胖、糖尿病和心血管疾病的保护作用。
1. Establishment and assessment of experimental type 2 diabetic cardiomyopathy rat model
Objective Diabetic cardiomyopathy (DC) is a specific and independent diabetic complication occurred in the absence of coronary artery disease or systemic hypertension. Clinical and epidemiological evidences have demonstrated the existence of diabetic cardiomyopathy in humans. Diabetic cardiomyopathy is diagnosed in diabetic patients in accordance with ventricular dysfunction in the absence of coronary atherosclerosis and hypertension and often occurs as an unknown asymptomatic heart disease, which counteracts clinical diagnosis and treatment. The major impediment of development of research in this area is the lack of appropriate animal models as well as the lack of standardized measures for phenotypes associated with diabetic cardiomyopathy. Importantly, animal model of diabetic cardiomyopathy should reflect the clinical features of patients and fulfill the definition of the disease before the onset of mechanism and medical studies. This study was to establish and evaluate a kind of experimental rat model of type 2 diabetic cardiomyopathy and assess the contribution of high fat-sucrose diet to the pathology.
Methods
Male Wistar rats (150g-180g) were randomly divided into 3 groups, including the control group, high sucrose-high fat group (HSF) and high sucrose-high fat with low dose streptozotocin (STZ) group (HSF-STZ). Rats in the control group were fed with normal food, while rats in the HSF and HSF-STZ groups were fed with high sucrose-high fat diet (consisted of 20% sucrose,10% lard,2.5% cholesterol,1% bile salt and 67.5% normal food) for totally 12 weeks. Blood of all rats were collected after 12-hour fasting to measure fasting blood glucose (FBG), total cholesterol (TCH) and triglyceride (TG) before high sucrose-high fat diet and after 4 weeks of feeding (the fifth week). Then rats in HSF-STZ group were injected intraperitoneally (i.p.) singly with STZ (resolved in citric acid-sodium citrate buffer, pH=4.5) at the dose of 30 mg/kg after 6 weeks' high sucrose-high fat diet feeding. FBG were tested at 72 hours after injection and FBG≥7.77 mmol/L was considered as standard of the establishment of diabetes mellitus. Rats in control and HSF groups were i.p. with vehicle (citric acid-sodium citrate buffer, pH=4.5). At the end of experiment (the eleventh week), indexes of heart rate (HR), stroke volume (SV) and cardiac output (CO) of rats were detected by impedance plethysmography (IPG) method and left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), the maximum rate of myocardial contraction and the maximum rate of myocardial diastole (±dp/dtmax) were measured by left ventricular catheterization by MP150 polygraph physiological signal recorder to evaluate cardiac function. The whole heart weight (HW), left ventricular weight (LVW), and ratios of HW/body weight (HW/BW), LVW/BW, interventricular septal thickness (IST), left ventricular wall thickness (LVWT) and left ventricular collagen concentration were measured to assess cardiac structure. Then artery blood of rats were gathered to detected FBG, glycosylated hemoglobin (HbA1c), glycosylated serum protein (GSP), TCH, high density lipoprotein (HDL) and nonesterified fatty acid (NEFA).
Results
Effects of high sucrose-high fat on blood sugar, blood lipid levels in rats. It showed no significant differences of blood glucose and lipid levels between each groups at the beginning of the experiment. After 4-week intake of high sucrose-high fat diet, serum TCH and TG of rats in HSF group significantly increased by 26% and 34%, and in HSF-STZ group significantly increased by 16% and 58%, when compared with the control group(P<0.05), whereas FBG didn't increase significantly.
Effects of high sucrose-high fat diet with STZ injection on lipid metabolism in rats. The blood lipid maintained high level after another 6 weeks of high sucrose-high fat diet intake. At same time, plasma NEFA of rats in HSF and HSF-STZ groups significantly increased by 131% and 100%, while HDL significantly reduced by 38% and 26%, respectively, when compared with the control group. TCH level of rats in HSF-STZ group was significantly increased by 44%, when compared with the control rats. The indexes of blood lipid indexes showed no significant difference between HSF-STZ-treated rats and HSF-treated rats.
Effects of high sucrose-high fat diet with STZ injection on blood sugar in rats. Plasma FBG, HbA1c and GSP significantly increased by 233%,35% and 28% respectively in HSF-STZ treated rats, when compared with control rats. However, values of blood sugar did not significantly increased in the HSF group, when compared with the control group.
Effects of high sucrose-high fat diet with STZ injection on cardiac function in rats. The high sucrose-high fat diet plus STZ treated rats showed the same hemodynamic characteristics of diabetic cardiomyopathy. Levels of LVSP, SV and CO significantly reduced by 15%,26% and 23%, while LVEDP and -dp/dtmax significantly increased by 44% and 29%, when compared with the control rats. Meanwhile, LVSP significantly decreased by 12%, and LVEDP significantly increased by 43% in the HSF-treated rats, when compared with the control rats. However, changes of±dp/dtmax, SV and CO did not get any statistical differences in HSF rats, when compared with the control rats. Interestingly, SV significantly decreased in HSF-STZ treated rats, when compared with HSF-treated rats.
Effects of high sucrose-high fat diet with STZ injection on cardiac structure in rats. Ratios of HW/BW and LVW/BW,IST and LVWT parameters, and collagen concentration significantly increased by 15%,10%,80%,33% and 18% in the HSF-STZ rats, when compared with the control rats. It also showed significant correlations between cardiac function and structure parameters.
Conclusion
In summary, experimental type 2 diabetic cardiomyopathy rat model can be established by high sucrose-high fat diet plus single low dosage of STZ injection. Diabetic cardiomyopathy rat model could be assessed efficiently and simply by synthetic indexes including glucose and lipid metabolism as well as heart function. The rat model demonstrated hyperglycemia, hyperlipidemia, and cardiac dysfunction especially diastolic dysfunction, which were similar to clinical symptoms.
2. Berberine attenuates cardiac dysfunction in experimental type 2 diabetic cardiomyopathy rat model
Objective
Berberine, an isoquinoline alkaloid, derived from medical herbs including Berberis, Hydrastis canadensis, Coptis chinensis Franch. and Cortex Phellodendri Chinensis, has antibacterial and anti-inflammatory activities. Recent studies demonstrated the reduction of blood sugar and lipids, increase in insulin sensitivity in type 1 and typer 2 diabetic animals, antiarrhythmia, as well as inhibition of cardiac hypertrophy with berberine treatment. Clinical researches have indicated that berberine can improve metabolic dysfunction and decrease ventricular premature complexes in the patients with dyslipidemia and congestive heart failure. Up to now, however, little attention has been focus on the role of berberine for treating diabetic cardiomyopathy. Hence our experiments were aimed to explore the effects of berberine on cardiac dysfunction and metabolic disorders in the experimental type 2 diabetic cardiomyopathy rat model induced by high sucrose-fat diet and streptozotocin.
Methods
Animal treatment. Rat model of experimental type 2 diabetic cardiomyopathy was induced as described in experiment 1. To speak simply, the control rats were fed with normal food and administrated with vehicle for totally 12 weeks. Rat model of experimental type 2 diabetic cardiomyopathy were fed with high sucrose-high fat diet (consisted of 20% sucrose,10% lard,2.5% cholesterol,1% bile salt and 66.5% normal food) for 6 weeks, then i.p. injection with streptozotocin at the dose of 30 mg/kg following a 12 h fast at the seventh week, and fed with special food as before for another 6 weeks. Rat model were daily intragastrically with relative medication including berberine (7.5 mg/kg,15 mg/kg and 30 mg/kg), Metformin (140 mg/kg), Rosiglitazone (2 mg/kg), and Captopril (45 mg/kg) at 72 h after STZ i.p. injection for totally consecutive 6 weeks.
Plasma profiles assessment. Whole blood samples were obtained from the right carotid artery of rats and collected in fresh vials containing anticoagulant, and plasma samples were prepared by centrifuging the whole blood for 10 min at 2000 g. Levels of fasting blood glucose, glycated hemoglobin, fructosamine, glycosylated serum protein, total cholesterol and triglyceride in plasma samples were determined using ultraviolet spectrophtometric method according to the manufacturer's protocol.
Cardiac function, biomarker and histology assessment. At the thirteenth week, rats were anesthetized with pentobarbital sodium (35 mg/kg, i.p.) following a 12 h fast. Stroke volume and cardiac output were detected by means of non-invasive impedance plethysmography. On completion of the cardiac output measurements, a catheter was positioned in the left ventricle via the right carotid artery for measurement of left ventricular systolic pressure, left ventricular end diastolic pressure, the maximum rate of myocardial contraction (+dp/dtmax) and the maximum rate of myocardial diastole (-dp/dtmax). Data were collected using MP150 systems. After that, rat hearts and left ventricles were obtained and weighted to calculate the ratios of heart weight and left ventricular weight to the body weight, respectively.
The homogenate of heart tissues were prepared in the physiological saline (1:9) and centrifuged for 10 min at 2000 g. The myocardial nonesterified free fatty acids were measured by the biochemical method.
Hydroxyproline concentration was determined in heart tissue by alkaline hydrolysis method. Tissue samples were hydrolyzed in 2 mol/L sodium hydroxide at 100℃for 1 h. Chloramine-T (0.05 mol/L) was used to oxidize for 10 min at room temperature (pH=6.0-6.8). Then Ehrlich's reagent was added to each sample and the samples were mixed and incubated at 65℃for 15 min. The absorbance of samples were read at 550nm using a spectrophotometer to determine the content of hydroxyproline. Left ventricular collagen content was estimated from its hydroxyproline concentration, with multiplying its value by 7.46, since the imino acid represents 13.4% of collagen. Levels of myocardial fatty acid transport protein-1, fatty acid transport proteins and fatty acidβ-oxidase were assessed by ELISA.
Then equator annulus of left ventricles were collected and placed in 10% buffered formalin. Sections (4μm) were cut and stained with hematoxylin and esosin (H&E). The left ventricular wall thickness and interventricular septum thickness were measured by Image-ProPlus 5.0 image analysis software (USA) on the H&E slices microscopically.
Cardiac PPAR a, PPAR y and GLUT4 mRNA expression assessment. Tissue samples obtained from left ventricles were rapidly frozen in liquid nitrogen and stored at -70℃prior to quantitative real-time (RT)-polymerase chain reaction (PCR) analysis. Total RNAs were isolated using TRIzol reagent according to the manufacturer's protocol, and then reverse transcribed to synthesize cDNA. The RT primers were designed by Prime 5.0 software.
Total Realtime PCR reaction system was performed in Rotor-Gene 3000 Realtime PCR instrument, as previously described. To allow for comparisons between samples and groups, quantities of all targets in test samples were normalized to the constitutive housekeeping gene glyceraldehyde phosphate dehydrogenase (GAPDH).
Cardiac PPARα, PPAR y and GLUT4 protein expression assessment. Total GLUT4, PPARa and PPARy protein expression in the heart homogenate extracts were determined by Western blot as described previously. GAPDH was probed as an internal loading control. Western blot band density analysis was made using ImageJ. Total GLUT4, PPARa and PPARy proteins were shown in arbitrary units.
Statistical analysis. All data were presented as mean±SEM and analyzed by one-way analysis of variance (ANOVA). Multiple group comparisons were made with least significant difference's (LSD) post hoc test by SPSS 17.0. Statistical significant difference was defined as a value of P< 0.05.
Results
Effects of berberine on general state, blood sugar and lipid levels in experimental type 2 diabetic cardiomyopathy rat model. The body weight of DC rat model significantly decreased at day 5 after i.p. with STZ and kept low level until the end of experiment, while the food and water intake significantly increased by 16% and 84%, when compared with the control rats. Berberine 30 mg/kg treatment could prevent the body weight reduction. In the rat model of diabetic cardiomyopathy, plasma fast blood glucose, glycated hemoglobin, glycosylated serum protein, fructosamine, total cholesterol, triglyceride and low density lipoprotein cholesterol significantly increased by 422%,40%,73%,86%, 205%,70% and 188% respectively, when compared with the control group. Berberine 30 mg/kg treatment significantly decreased plasma FBG, HbA1c, GSP, FMN, TCH, TG and LDL by 69%,40%,46%,40%,42%,42% and 40%, respectively, when compared with the drug-untreated rat model of DC. Metformin 140 mg/kg treatment significantly decreased FBG, HbA1c, GSP, FMN and TG levels by 67%,34%,42%,34% and 41% respectively in DC rat model. Rosiglitazone 2 mg/kg treatment could reduce plasma FBG, HbA1c, TG and LDL by 36%,24%,40% and 37%, when compared with DC rat model.
Effects of berberine on cardiac function in experimental type 2 diabetic cardiomyopathy rat model. The rats treated with high fat-high sucrose plus STZ showed the same hemodynamic characteristics of diabetic cardiomyopathy. Cardiac output, left ventricular systolic pressure and +dp/dtmax in DC rat model significantly decreased by 36%,18% and 45%, while left ventricular end diastolic pressure and -dp/dtmax significantly increase by 44% and 38%, when compared with normal rats. Berberine 30 mg/kg could significantly increase CO, LVSP, and +dp/dtmax by 60%,14% and 81%, and decrease LVEDP and-dp/dtmax by 80% and 55%, while Berberine 15 mg/kg only increased LVSP significantly, when compared with the drug-untreated DC rat model. Metformin 140 mg/kg treatment significantly increased CO and +dp/dtmax by 71% and 60%, while Captoprile 45 mg/kg treatment could increase CO, LVSP,+dp/dtmax by 54%,15% and 77%, and decrease -dp/dt max by 52%, when compared with drug-untreated DC rat model.
Effects of berberine on cardiac structure in experimental type 2 diabetic cardiomyopathy rat model. When rats treated with high fat-high sucrose food and STZ, the ratios of heart weight and left ventricular weight to the body weight, interventricular septum thickness, left ventricular thickness, and myocardial collagen content were significantly increased by 11%,10%,78%,33% and 22%. Berberine 30 mg/kg treatment decreased HW/BW, LVW/BW,IST, LVWT and collagen content by 6%,9%,20%,46% and 32% respectively in the DC rats, when compared with the drug-untreated rat model. Metformin, Rosiglitazone as well as Captopril treatment could significantly decrease IST by 26%,47% and 40% in the DC rat model.
Effects of berberine on cardiac structure in experimental type 2 diabetic cardiomyopathy rat model. Levels of myocardial nonesterified free fatty acid and enzymes involved in fatty acids transport and oxidation were measured. Myocardial nonesterified fatty acid in the DC rat model was significantly increased by 69%, while fatty acid transport protein-1, fatty acid transport proteins and fatty acidβ-oxidase were decreased by 68%,22% and 47%, respectively, when compared with the normal rats. Berberine at the dosage of 7.5, 15 and 30 mg/kg and Metformin 140 mg/kg treatment significant reduced myocardial NEFA by 34%,27% and 25% respectively, when compared with the rat model of DC. Meanwhile, Berberine 30 mg/kg treatment could significantly increase FATP-1, FATPs, and FA-β-oxidase by 159%,56% and 91%, when compared with the drug-untreated rat model.
Cardiac PPAR a, PPAR y and GLUT4 mRNA expression. Genes involved in cardiac glucose and lipid metabolism was evaluated by quantitative real-time PCR. As expected, cardiac mRNA expression of PPAR y and GLUT4 mRNA expression reduced by 38% and 34%, while PPAR a mRNA gene expression increased by 80% in the DC rat model, when compared with normal rats. Berberine 30 mg/kg treatment increase PPAR y and GLUT4 mRNA expression by 50% and 32%, and decreased PPAR a mRNA levels by 54% in the DC rat model, when compared with drug-untreated rat model.
Cardiac PPARα, PPAR y and GLUT4 protein expression. Protein expression of PPAR y and GLUT4 reduced by 40% and 68% respectively in the DC rat model, when compared with control rats. Berberine treatment significantly increased PPAR y and GLUT4 protein expression by 83% and 133% in the DC rat model, when compared with the drug-untreated rat model. However, berberine at the dosage of 30 mg/kg did not show any detectable changes in the cardiac PPAR a protein expression.
Conclusion
Phenotypes such as hyperglycemia, hypercholesterolemia, cardiac dysfunction and left ventricular hypertrophy, cardiac lipid accumulation, which mimics to the diabetic cardiomyopathy, were found in the rat model induced by high fat-high sucrose food plus streptozotocin treatment. Berberine treatment could effectively recover the diastolic and systolic dysfunction, inhibit the cardiac left ventricular hypertrophy, lower plasma sugar and lipids levels in the DC rat model. It could also alleviate cardiac lipid accumulation, increase intracellular fatty acid transport proteins and fatty acid beta-oxidase, and impressively increase mRNA and protein expression of PPAR y and GLUT4 and repress PPAR a gene expression, indicating a protective effect of berberine on experimental diabetic cardiomyopathy.
3. Inhibitory differentiation effect of berberine on 3T3-L1 fibroblasts
Objective
To study the effect of berberine on preadipocyte differentiation, lipid accumulation and adipokines secretory in the murine 3T3-L1 cell line.
Methods
Cell culture and treatments. Murine 3T3-L1 preadipocyte were grown on FALCON 6-well plates in a 5% CO2 atmosphere at 37℃and maintained in low glucose Dullbecco's Modified Eagle's medium supplemented with 10% fetal bovine serum,100 U/mL penicillin, and 100μg/mL streptomycin. The 2-day postconfluent 3T3-L1 cells (designed as Day 0) were incubated with 10% FBS/high glucose DMEM and antibiotics,500μM 3-isobutyl-1-methylxanthine, 1μM dexamethasone, and 5μg/ml insulin for 3 days (Day 0-2). Then the cells were incubated for 2 days in 10% FBS/HG-DMEM with insulin (Day 3-4), and, thereafter incubated in 10% FBS/HG-DMEM that was changed once every 2 days (Day 5-9). Cells receiving berberine chloride were given 10% FBS/HG-DMEM and insulin containing a final concentrantion of 5,10 and 20μM berberine in DMSO at Day 3 and Day4, then medium changed to only 10% FBS/HG-DMEM with berberine for last 5 days (Day 5-9).
Oil-Red-O staining. After differentiation (Day 9), cells were stained with Oil-Red-O to detect droplets in adipocytes. Cells were washed 3 times with phosphate buffered saline (PBS), fixed with 4% paraformaldehyde for 30 min and then stained with 1.8 mg/ml Oil-Red-O in 60% isopropanol for 30 min. Cells were washed with 60% isopropanol until colorless and observed under a microscope in PBS. Stained oil droplets in the cells were dissolved by Nonidet-P40 (4%, v/v, diluted in isopropanol) with gentle agitation for 5 min. Supernatant was measured with a spectrophotometer at 500 nm.
Reverse Transcription-Polymerase Chain Reaction. Total RNA was extracted from cultured 3T3-L1 adipocyte (Day 8) and preadipocyte by using QIAGEN RNeasy Mini Kit. Complementary DNA was generated from 2μg of total RNA and synthesized by using High Capacity cDNA Reverse Transcription Kit. The PCR conditions were as follows:for glyceraldehydes-3-phosphoate dehydrogenase (GAPDH) and adiponectin,25 cycles of 95℃for 30s,55℃for 30s,72℃for 30s; for resistin,27 cycles of 95℃for 30s,55℃for 30s,72℃for 30s; for peroxisome proliferator-activated receptor-y (PPAR y), adipocyte fatty acid binding protein (aP2), fatty acid synthase (FAS), angiotensinogen (AGT), monocyte chemoattractant protein 1 (MCP-1),28 cycles of 95℃for 30s,55℃for 30s,72℃for 30s; for CCAAT/enhancer binding protein (3 (C/EBP P), plasminogen activator inhibitor-1 (PAI-1),30 cycles of 95℃for 30s,55℃for 30s,72℃for 30s; for C/EBP a and leptin,31 cycles of 95℃for 30s,55℃for 30s,72℃for 30s. To allow for comparisons between samples and groups, quantities of all targets in test samples were normalized to GAPDH.
Results
Inhibitory effects of berberine on triglyceride content and lipid accumulation in 3T3-L1 cells. Berberine at the dosage of 5μM,10μM and 20μM significantly decreased triglyceride content (26%,37%, and 43%, respectively) and lipid accumulation of 3T3-L1 adipocyte in a dose-dependent manner.
Effects of berberine on transcription factors during differentiation process in 3T3-L1 cells. Berberine 10μM and 20μM significantly decreased C/EBP a (21% and 47%) and PPAR y mRNA (21% and 55%) gene expression in 3T3-L1 adipocyte in a dose dependent manner. Berberine at a dose of 20μM significantly reduced C/EBPβmRNA gene expression by 16%, whereas 5μM significantly increased C/EBP (3 mRNA gene expression by 21%.
Effects of berberine on expression of genes involved in lipid metabolism. Berberine at dosage of 10 and 20μM significantly decreased aP2 mRNA expression (18% and 40%). Berberine 20μM significantly reduced FAS mRNA expression by 18%, however, berberine 5μM significantly increased FAS gene expression by 15%.
Effects of berberine on adipokines (adiponectin, leptin, resistin, MCP-1, PAI-1 AGT) in 3T3-L1 cells. Berberine 5μM,10μM and 20μM significantly decreased adiponectin (9%,46% and 85%), leptin (33%,75% and 100%) and resistin (13%,63% and 82%) mRNA expression of 3T3-L1 cells in a dose dependent manner. Berberine 10μM and 20μM significantly decreased AGT mRNA expression (15% and 17%). Berberine in dose of 20μM caused significant reduction of PAI-1 (12%) and MCP-1 (28%) mRNA expression, whereas 5μM significantly increased PAI-1 (10%) and MCP-1 (26%) mRNA expression in 3T3-L1 adipocyte.
Conclusion
Berberine inhibited triglyceride and lipid accumulation in 3T3-L1 adipocyte. Berberine could inhibit differentiation of 3T3-L1 fibroblast via reducing transcription factors such as C/EBPβ, C/EBP a and PPAR y and their downstream genes aP2 and FAS. In term of inhibitory effect on differentiation in 3T3-L1 cells of berberine, adipokines including adiponectin, leptin, resistin, and AGT also showed significant decrease with berberine treatment, which might indicate anti-obesity action as well as cardiovascular protective effect of berberine. However, the reduction effect of berberine on MCP-1 and PAI-1 mRNA expression might be independent of differentiation inhibitory action.
目的：建立和评价实验性2型糖尿病心肌病(DC)大鼠模型,探究高糖脂饮食在模型诱导过程中的作用。方法：将雄性Wistar大鼠随机分成正常对照组(Control),高糖脂饮食组(HSF)和高糖脂饮食负荷小剂量链脲佐菌素组(HSF-STZ).Control大鼠喂养常规饲料12周,HSF大鼠喂饲高糖高脂饲料12周,HSF-STZ大鼠喂饲高糖高脂饲料6周后一次性腹腔注射30 mg/kg STZ并继续给予高糖高脂饲料6周以诱导2型糖尿病心肌病病变。监测大鼠一般状态；容积阻抗法测定心排量；左心室插管测定血流动力学指标；称重法测定大鼠心脏重量,计算心重指数(HW/BW)和左心室肥厚指数(LVW/BW):心脏赤道面横切作常规HE染色,观察病理变化并计算左心室前壁(LVWT)和室间隔厚度(IST)；生化法测定血液糖、脂代谢指标和心肌组织胶原含量。结果：①HSF-STZ大鼠腹腔注射STZ并继续喂养6周后,与正常大鼠比较,进食量和饮水量分别显著增加16%和84%。②与Control大鼠比较,HSF大鼠喂养高糖高脂饲料4周后,总胆固醇(TCH,26%)和甘油三脂(TG,34%)水平显著升高；HSF-STZ大鼠腹腔注射STZ并继续喂养6周后血浆TCH(44%)、血浆游离脂肪酸(NEFA,100%)和心肌组织NEFA(69%)水平显著升高,高密度脂蛋白值(HDL)降低26%；同时血浆空腹血糖(FBG,233%)、糖化血红蛋白(HbAlc,35%)和糖化血清蛋白(GSP,28%)明显增加。③与Control大鼠比较,HSF-STZ大鼠左心室收缩压(LVSP,15%)、每搏输出量(SV,26%)和心排量(CO,23%)显著降低,左心室舒张末期压力(LVEDP,44%)和左心室最大舒张速率(一dp/dtmax,29%)明显升高。④与Control大鼠比较,HSF-STZ大鼠HW/BW和LVW/BW指数分别升高15%和10%。⑤HE染色结果显示HSF-STZ大鼠心肌纤维排列紊乱、断裂,心肌细胞肥大,细胞核边缘不清、融合,甚至消失；LVWT(33%).IST值(80%)和胶原含量(18%)显著增加。结论：①Wistar大鼠高糖高脂饲料喂养负荷链脲佐菌素(30 mg/kg)腹腔注射可建立实验性2型糖尿病心肌病大鼠模型。②高糖高脂饲料喂养可诱导肥胖和高血脂,在2型糖尿病心肌病大鼠模型发病过程中有重要作用。
第二部分小檗碱治疗2型糖尿病心肌病作用及机制整体实验研究
目的：建立实验性2型糖尿病心肌病大鼠模型,观察小檗碱对模型大鼠机体一般状况,血糖、血脂和心脏功能和结构,心肌组织NEFA、脂肪酸转运和氧化酶含量,以及心肌组织过氧化物增殖体激活受体(PPAR)α、PPARγ和葡萄糖转运体4 (GLUT4) mRNA基因和蛋白表达的影响。方法：糖尿病心朋病大鼠模型(DC rat model)建立同第一部分,小檗碱(Berberine)分为7.5、15和30 mg/kg组,阳性药包括二甲双胍(Metformin) 140 mg/kg组、罗格列酮(Rosiglitazone) 2 mg/kg组和卡托普利(Captopril) 45 mg/kg组,另设正常对照组(Control)。治疗组动物从注射STZ后72小时按相应剂量开始灌胃给药6周。定期监测各组大鼠一般体征变化；生化法检测血糖和血脂,以及心朋组织胶原(Collagen)、肌酸激酶(CK)和NEFA含量；容积阻抗法测定心排量,左心室插管测定血流动力学指标；称重法测定大鼠心脏重量,计算HW/BW和LVW/BW;心脏作常规HE染色,计算LVWT和IST; Elisa去检测心肌红织脂肪酸转运蛋白-1(FATP-1)、脂肪酸转运蛋白(FATPs)和脂肪酸β氧化酶(FA-β-oxidase)含量。实时定量PCR检测心肌组织PPARα、PPARγ和GLUT mRNA基因表达；Western blot去检测PPAR a、PPAR 7和GLUT4蛋白表达。结果：①Berberine 30 mg/kg和Metformin 140 mg/kg可显著抑制DC rat mode体重降低；Metformin 140 mg/kg降低模型大鼠饮水量10%,其余药物均未明显改变动物模型的饮食量。②与DC rat model比较,小檗碱30 mg/kg和Metformi 140 mg/kg可显著降低FBG(69%和67%)、GSP(40%和34%)、HbAlc(46%和42%)和果糖胺(FMN)(40%和34%)含量；Rosiglitazone 2 mg/kg可显著降低降低FBG(36%)和HbAl。(24%)；Captopril 45 mg/kg可明显降低HbAl(31%)。③与DC rat model比较,Berberine 30 mg/kg组动物TCH(42%)、TG(42%)和低密度脂蛋白(LDL)值(40%)显著降低；Rosiglitazone 2 mg/k可显著降低TG(49%)和LDL(37%)水平；Metformin显著降低TG值达41%④与DC rat model比较,小檗碱30 mg/kg组动物LVSP (14%)和左心室最夕收缩速率(+dp/dtmax,81%)明显增加,LVEDP (80%)和-dp/dtmax (55%)显著降低,心排量增加60%; Captopril 45 mg/kg组LVSP(15%)和+dp/dtmax(77%显著增加,-dp/dtmax降低52%,心排量增加54%；Metformin 140 mg/kg组动物+dp/dtmax上升60%,心排量增加71%。⑤与DC大鼠模型比较,小檗碱30 mg/k治疗可明显降低HW/BW (6%)和LVW/BW (9%)指数、心肌组织胶原含量(32%)、IST(20%)和LVWT (46%)值；Metformin 140 mg/kg显著降低术型大鼠心肌胶原含量(26%)和IST水平(26%)。⑥光镜下观察左心室纵切片HE染色结果显示,Berberine 30 mg/kg.Metformin 140 mg/kg和Captopril 45 mg/kg治疗后,心肌组织病理损伤有明显的改善,心肌细胞排列较规则,细胞核清晰可见。⑦与正常大鼠比较,DC rat model心肌组织NEFA和CK含量分别显著升高69%和95%；与DC rat model比较,小檗碱7.5、15和30 mg/kg组动物心肌NEFA含量分别降低34%、27%和25%,阳性药Metformin 140 mg/kg(36%)和Captopril 45 mg/kg(24%)组动物心肌组织NEFA含量也显著下降；Berberine 30 mg/kg.Metformin.Rosiglitazone和Captopril组动物心肌组织CK水平分别降低20%、39%、26%和18%；另外,DC rat model心肌组织FATP一1 (68%).FATPs(22%)和FA-p-Oxidase(47%)含量较正常大鼠比较显著降低,小檗碱30 mg/kg治疗后,大鼠心肌组织FATP-1、FATPs和FA-β-oxidase含量分别提高了159%、56%和91%。⑧与正常大鼠比较,DC rat model心肌组织PPARαmRNA表达升高了80%,Berberine 30mg/kg(54%).Metformin 140mg/kg(40%).Rosiglitazone 2 mg/kg(47%)及Captopril 45 mg/kg(38%)可显著下调心肌组织的PPARαmRNA表达。⑨与正常大鼠比较,DC rat model心肌组织PPARγmRNA基因(38%)和蛋白(40%)表达明显降低；Berberine 30 mg/kg组动物PPARγ基因(50%)和蛋白(83%)表达与大鼠模型比较显著升高；同时,DC rat model心肌组织GLUT4 mRNA基因(34%)和蛋白(68%)表达明显比正常大鼠降低；与DC rat model比较,Berberine 30 mg/kg(32%)和Captopril 45 mg/kg(36%)组动物GLUT4 mRNA基因表达明显升高,另外Berberine 30 mg/kg(133%).Metformin 140 mg/kg(208%)和Rosiglitazone 2 mg/kg(166%)组动物GLUT4蛋白表达也显著升高。结论：小檗碱可显著改善高糖高脂负荷小剂量STZ诱导的实验性2型糖尿病心肌病大鼠模型心脏舒张功能和收缩功能损伤,并且抑制心肌胶原积聚和左心室重构；同时还可以显著降低大鼠模型血糖、血脂各项指标,并且对糖尿病大鼠一般体征状态有明显改善作用；其作用机制可能与提高心肌组织转录调控因子PPARγ和GLUT4 mRNA基因和蛋白表达,降低PPARαmRNA基因表达,上调下游目的因子FATP-1、FATPs和FA-β-oxidase含量,改善心肌组织脂肪酸的转运氧化能力,提高葡萄糖的转运能力,抑制心肌组织脂质积聚有关。
第三部分小檗碱对3T3-L1前脂肪细胞分化、脂肪积聚和脂肪因子分泌的影响
目的：培养小鼠3T3-L1前脂肪细胞,观察小檗碱对前脂肪细胞向脂肪细胞分化、细胞甘油三脂积聚以及脂肪因子基因表达的影响。方法：培养小鼠3T3-L1细胞,用含10%胎牛血清(FBS)、100U/mL青霉素、100μg/mL链霉素、5μg/mL胰岛素、1μM地塞米松和500μM 3-异丁基-1-甲基黄嘌呤的高糖DMEM培养基诱导分化(Day 0),为期3天(Day 0-Day 2).细胞于Day 3,Day 5和Day 7用小檗碱(5μM、10μM和20μM)处理,共给药3次,Day 8进入实验。未分化的细胞称为前脂肪细胞(Preadipocyte)。油红-O染色测定细胞内脂滴积聚,观察细胞内脂滴大小。生化法测定细胞内蛋白和甘油三脂含量。逆转录聚合酶链反应法(RT-PCR)检测调控前脂肪细胞分化基因和脂质代谢相关基因CCAAT/增强子结合蛋白(C/EBP)α、C/EBPβ、PPARγ、脂肪细胞脂质结合蛋白(aP2)和脂肪酸合成酶(FAS),以及脂肪因子脂联素(adiponectin)、瘦素(leptin)、抵抗素(resistin)、血管紧张素原(AGT)、纤溶酶原激活物抑制剂-1(PAI-1)和单核巨噬细胞趋化蛋白-1(MCP-1)基因表达。结果：①小檗碱(5、10和20μM)呈剂量依赖性分别降低脂肪细胞TG值26%、37%和43%,抑制脂质积聚。②小檗碱10μM和20μM可降低脂肪细胞C/EBP a(21%和47%)和PPAR y mRNA(21%和55%)基因表达；小檗碱20μM显著降低C/EBPβmRNA基因表达16%。③小檗碱10μM和20μM分别降低aP2基因18%和40%；20μM显著降低FAS基因表达18%。④前脂肪细胞中未见adiponectin. leptin和resistin基因表达,而脂肪细胞中adiponectin、leptin和resistin mRNA表达明显升高(P<0.001),小檗碱5μM、10μM和20μM呈剂量依赖性分别降低adiponectin(9%、46%和85%)、leptin(33%、75%和100%)和resistin(13%、63%和82%)在脂肪细胞中的表达。⑤3T3-L1前脂肪细胞分化为脂肪细胞后,细胞内AGT mRNA基因表达明显升高84%,小檗碱10μM和20μM分别降低脂肪细胞中AGT mRNA表达15%和24%。⑥3T3-L1前脂肪细胞与脂肪细胞均可以分泌PAI-1和MCP-1,且二者比较,PAI-1和MCP-1 mRNA基因表达并没有明显的差异；小檗碱20μM明显降低脂肪细胞内PAI-1(12%)和MCP-1 mRNA (28%)基因表达。结论：小檗碱可抑制3T3-L1前脂肪细胞向脂肪细胞分化,降低细胞内TG含量和脂滴积聚,这与其抑制细胞分化过程中转录因子C/EBPβ、C/EBP a和PPAR y以及下游与脂肪代谢调节相关的基因aP2和FAS基因表达有关。小檗碱可下调脂肪因子adiponectin、leptin、resistin、AGT、PAI-1和MCP-1基因表达,进一步证实小檗碱对肥胖、糖尿病和心血管疾病的保护作用。
1. Establishment and assessment of experimental type 2 diabetic cardiomyopathy rat model
Objective Diabetic cardiomyopathy (DC) is a specific and independent diabetic complication occurred in the absence of coronary artery disease or systemic hypertension. Clinical and epidemiological evidences have demonstrated the existence of diabetic cardiomyopathy in humans. Diabetic cardiomyopathy is diagnosed in diabetic patients in accordance with ventricular dysfunction in the absence of coronary atherosclerosis and hypertension and often occurs as an unknown asymptomatic heart disease, which counteracts clinical diagnosis and treatment. The major impediment of development of research in this area is the lack of appropriate animal models as well as the lack of standardized measures for phenotypes associated with diabetic cardiomyopathy. Importantly, animal model of diabetic cardiomyopathy should reflect the clinical features of patients and fulfill the definition of the disease before the onset of mechanism and medical studies. This study was to establish and evaluate a kind of experimental rat model of type 2 diabetic cardiomyopathy and assess the contribution of high fat-sucrose diet to the pathology.
Methods
Male Wistar rats (150g-180g) were randomly divided into 3 groups, including the control group, high sucrose-high fat group (HSF) and high sucrose-high fat with low dose streptozotocin (STZ) group (HSF-STZ). Rats in the control group were fed with normal food, while rats in the HSF and HSF-STZ groups were fed with high sucrose-high fat diet (consisted of 20% sucrose,10% lard,2.5% cholesterol,1% bile salt and 67.5% normal food) for totally 12 weeks. Blood of all rats were collected after 12-hour fasting to measure fasting blood glucose (FBG), total cholesterol (TCH) and triglyceride (TG) before high sucrose-high fat diet and after 4 weeks of feeding (the fifth week). Then rats in HSF-STZ group were injected intraperitoneally (i.p.) singly with STZ (resolved in citric acid-sodium citrate buffer, pH=4.5) at the dose of 30 mg/kg after 6 weeks' high sucrose-high fat diet feeding. FBG were tested at 72 hours after injection and FBG≥7.77 mmol/L was considered as standard of the establishment of diabetes mellitus. Rats in control and HSF groups were i.p. with vehicle (citric acid-sodium citrate buffer, pH=4.5). At the end of experiment (the eleventh week), indexes of heart rate (HR), stroke volume (SV) and cardiac output (CO) of rats were detected by impedance plethysmography (IPG) method and left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), the maximum rate of myocardial contraction and the maximum rate of myocardial diastole (±dp/dtmax) were measured by left ventricular catheterization by MP150 polygraph physiological signal recorder to evaluate cardiac function. The whole heart weight (HW), left ventricular weight (LVW), and ratios of HW/body weight (HW/BW), LVW/BW, interventricular septal thickness (IST), left ventricular wall thickness (LVWT) and left ventricular collagen concentration were measured to assess cardiac structure. Then artery blood of rats were gathered to detected FBG, glycosylated hemoglobin (HbA1c), glycosylated serum protein (GSP), TCH, high density lipoprotein (HDL) and nonesterified fatty acid (NEFA).
Results
Effects of high sucrose-high fat on blood sugar, blood lipid levels in rats. It showed no significant differences of blood glucose and lipid levels between each groups at the beginning of the experiment. After 4-week intake of high sucrose-high fat diet, serum TCH and TG of rats in HSF group significantly increased by 26% and 34%, and in HSF-STZ group significantly increased by 16% and 58%, when compared with the control group(P<0.05), whereas FBG didn't increase significantly.
Effects of high sucrose-high fat diet with STZ injection on lipid metabolism in rats. The blood lipid maintained high level after another 6 weeks of high sucrose-high fat diet intake. At same time, plasma NEFA of rats in HSF and HSF-STZ groups significantly increased by 131% and 100%, while HDL significantly reduced by 38% and 26%, respectively, when compared with the control group. TCH level of rats in HSF-STZ group was significantly increased by 44%, when compared with the control rats. The indexes of blood lipid indexes showed no significant difference between HSF-STZ-treated rats and HSF-treated rats.
Effects of high sucrose-high fat diet with STZ injection on blood sugar in rats. Plasma FBG, HbA1c and GSP significantly increased by 233%,35% and 28% respectively in HSF-STZ treated rats, when compared with control rats. However, values of blood sugar did not significantly increased in the HSF group, when compared with the control group.
Effects of high sucrose-high fat diet with STZ injection on cardiac function in rats. The high sucrose-high fat diet plus STZ treated rats showed the same hemodynamic characteristics of diabetic cardiomyopathy. Levels of LVSP, SV and CO significantly reduced by 15%,26% and 23%, while LVEDP and -dp/dtmax significantly increased by 44% and 29%, when compared with the control rats. Meanwhile, LVSP significantly decreased by 12%, and LVEDP significantly increased by 43% in the HSF-treated rats, when compared with the control rats. However, changes of±dp/dtmax, SV and CO did not get any statistical differences in HSF rats, when compared with the control rats. Interestingly, SV significantly decreased in HSF-STZ treated rats, when compared with HSF-treated rats.
Effects of high sucrose-high fat diet with STZ injection on cardiac structure in rats. Ratios of HW/BW and LVW/BW,IST and LVWT parameters, and collagen concentration significantly increased by 15%,10%,80%,33% and 18% in the HSF-STZ rats, when compared with the control rats. It also showed significant correlations between cardiac function and structure parameters.
Conclusion
In summary, experimental type 2 diabetic cardiomyopathy rat model can be established by high sucrose-high fat diet plus single low dosage of STZ injection. Diabetic cardiomyopathy rat model could be assessed efficiently and simply by synthetic indexes including glucose and lipid metabolism as well as heart function. The rat model demonstrated hyperglycemia, hyperlipidemia, and cardiac dysfunction especially diastolic dysfunction, which were similar to clinical symptoms.
2. Berberine attenuates cardiac dysfunction in experimental type 2 diabetic cardiomyopathy rat model
Objective
Berberine, an isoquinoline alkaloid, derived from medical herbs including Berberis, Hydrastis canadensis, Coptis chinensis Franch. and Cortex Phellodendri Chinensis, has antibacterial and anti-inflammatory activities. Recent studies demonstrated the reduction of blood sugar and lipids, increase in insulin sensitivity in type 1 and typer 2 diabetic animals, antiarrhythmia, as well as inhibition of cardiac hypertrophy with berberine treatment. Clinical researches have indicated that berberine can improve metabolic dysfunction and decrease ventricular premature complexes in the patients with dyslipidemia and congestive heart failure. Up to now, however, little attention has been focus on the role of berberine for treating diabetic cardiomyopathy. Hence our experiments were aimed to explore the effects of berberine on cardiac dysfunction and metabolic disorders in the experimental type 2 diabetic cardiomyopathy rat model induced by high sucrose-fat diet and streptozotocin.
Methods
Animal treatment. Rat model of experimental type 2 diabetic cardiomyopathy was induced as described in experiment 1. To speak simply, the control rats were fed with normal food and administrated with vehicle for totally 12 weeks. Rat model of experimental type 2 diabetic cardiomyopathy were fed with high sucrose-high fat diet (consisted of 20% sucrose,10% lard,2.5% cholesterol,1% bile salt and 66.5% normal food) for 6 weeks, then i.p. injection with streptozotocin at the dose of 30 mg/kg following a 12 h fast at the seventh week, and fed with special food as before for another 6 weeks. Rat model were daily intragastrically with relative medication including berberine (7.5 mg/kg,15 mg/kg and 30 mg/kg), Metformin (140 mg/kg), Rosiglitazone (2 mg/kg), and Captopril (45 mg/kg) at 72 h after STZ i.p. injection for totally consecutive 6 weeks.
Plasma profiles assessment. Whole blood samples were obtained from the right carotid artery of rats and collected in fresh vials containing anticoagulant, and plasma samples were prepared by centrifuging the whole blood for 10 min at 2000 g. Levels of fasting blood glucose, glycated hemoglobin, fructosamine, glycosylated serum protein, total cholesterol and triglyceride in plasma samples were determined using ultraviolet spectrophtometric method according to the manufacturer's protocol.
Cardiac function, biomarker and histology assessment. At the thirteenth week, rats were anesthetized with pentobarbital sodium (35 mg/kg, i.p.) following a 12 h fast. Stroke volume and cardiac output were detected by means of non-invasive impedance plethysmography. On completion of the cardiac output measurements, a catheter was positioned in the left ventricle via the right carotid artery for measurement of left ventricular systolic pressure, left ventricular end diastolic pressure, the maximum rate of myocardial contraction (+dp/dtmax) and the maximum rate of myocardial diastole (-dp/dtmax). Data were collected using MP150 systems. After that, rat hearts and left ventricles were obtained and weighted to calculate the ratios of heart weight and left ventricular weight to the body weight, respectively.
The homogenate of heart tissues were prepared in the physiological saline (1:9) and centrifuged for 10 min at 2000 g. The myocardial nonesterified free fatty acids were measured by the biochemical method.
Hydroxyproline concentration was determined in heart tissue by alkaline hydrolysis method. Tissue samples were hydrolyzed in 2 mol/L sodium hydroxide at 100℃for 1 h. Chloramine-T (0.05 mol/L) was used to oxidize for 10 min at room temperature (pH=6.0-6.8). Then Ehrlich's reagent was added to each sample and the samples were mixed and incubated at 65℃for 15 min. The absorbance of samples were read at 550nm using a spectrophotometer to determine the content of hydroxyproline. Left ventricular collagen content was estimated from its hydroxyproline concentration, with multiplying its value by 7.46, since the imino acid represents 13.4% of collagen. Levels of myocardial fatty acid transport protein-1, fatty acid transport proteins and fatty acidβ-oxidase were assessed by ELISA.
Then equator annulus of left ventricles were collected and placed in 10% buffered formalin. Sections (4μm) were cut and stained with hematoxylin and esosin (H&E). The left ventricular wall thickness and interventricular septum thickness were measured by Image-ProPlus 5.0 image analysis software (USA) on the H&E slices microscopically.
Cardiac PPAR a, PPAR y and GLUT4 mRNA expression assessment. Tissue samples obtained from left ventricles were rapidly frozen in liquid nitrogen and stored at -70℃prior to quantitative real-time (RT)-polymerase chain reaction (PCR) analysis. Total RNAs were isolated using TRIzol reagent according to the manufacturer's protocol, and then reverse transcribed to synthesize cDNA. The RT primers were designed by Prime 5.0 software.
Total Realtime PCR reaction system was performed in Rotor-Gene 3000 Realtime PCR instrument, as previously described. To allow for comparisons between samples and groups, quantities of all targets in test samples were normalized to the constitutive housekeeping gene glyceraldehyde phosphate dehydrogenase (GAPDH).
Cardiac PPARα, PPAR y and GLUT4 protein expression assessment. Total GLUT4, PPARa and PPARy protein expression in the heart homogenate extracts were determined by Western blot as described previously. GAPDH was probed as an internal loading control. Western blot band density analysis was made using ImageJ. Total GLUT4, PPARa and PPARy proteins were shown in arbitrary units.
Statistical analysis. All data were presented as mean±SEM and analyzed by one-way analysis of variance (ANOVA). Multiple group comparisons were made with least significant difference's (LSD) post hoc test by SPSS 17.0. Statistical significant difference was defined as a value of P< 0.05.
Results
Effects of berberine on general state, blood sugar and lipid levels in experimental type 2 diabetic cardiomyopathy rat model. The body weight of DC rat model significantly decreased at day 5 after i.p. with STZ and kept low level until the end of experiment, while the food and water intake significantly increased by 16% and 84%, when compared with the control rats. Berberine 30 mg/kg treatment could prevent the body weight reduction. In the rat model of diabetic cardiomyopathy, plasma fast blood glucose, glycated hemoglobin, glycosylated serum protein, fructosamine, total cholesterol, triglyceride and low density lipoprotein cholesterol significantly increased by 422%,40%,73%,86%, 205%,70% and 188% respectively, when compared with the control group. Berberine 30 mg/kg treatment significantly decreased plasma FBG, HbA1c, GSP, FMN, TCH, TG and LDL by 69%,40%,46%,40%,42%,42% and 40%, respectively, when compared with the drug-untreated rat model of DC. Metformin 140 mg/kg treatment significantly decreased FBG, HbA1c, GSP, FMN and TG levels by 67%,34%,42%,34% and 41% respectively in DC rat model. Rosiglitazone 2 mg/kg treatment could reduce plasma FBG, HbA1c, TG and LDL by 36%,24%,40% and 37%, when compared with DC rat model.
Effects of berberine on cardiac function in experimental type 2 diabetic cardiomyopathy rat model. The rats treated with high fat-high sucrose plus STZ showed the same hemodynamic characteristics of diabetic cardiomyopathy. Cardiac output, left ventricular systolic pressure and +dp/dtmax in DC rat model significantly decreased by 36%,18% and 45%, while left ventricular end diastolic pressure and -dp/dtmax significantly increase by 44% and 38%, when compared with normal rats. Berberine 30 mg/kg could significantly increase CO, LVSP, and +dp/dtmax by 60%,14% and 81%, and decrease LVEDP and-dp/dtmax by 80% and 55%, while Berberine 15 mg/kg only increased LVSP significantly, when compared with the drug-untreated DC rat model. Metformin 140 mg/kg treatment significantly increased CO and +dp/dtmax by 71% and 60%, while Captoprile 45 mg/kg treatment could increase CO, LVSP,+dp/dtmax by 54%,15% and 77%, and decrease -dp/dt max by 52%, when compared with drug-untreated DC rat model.
Effects of berberine on cardiac structure in experimental type 2 diabetic cardiomyopathy rat model. When rats treated with high fat-high sucrose food and STZ, the ratios of heart weight and left ventricular weight to the body weight, interventricular septum thickness, left ventricular thickness, and myocardial collagen content were significantly increased by 11%,10%,78%,33% and 22%. Berberine 30 mg/kg treatment decreased HW/BW, LVW/BW,IST, LVWT and collagen content by 6%,9%,20%,46% and 32% respectively in the DC rats, when compared with the drug-untreated rat model. Metformin, Rosiglitazone as well as Captopril treatment could significantly decrease IST by 26%,47% and 40% in the DC rat model.
Effects of berberine on cardiac structure in experimental type 2 diabetic cardiomyopathy rat model. Levels of myocardial nonesterified free fatty acid and enzymes involved in fatty acids transport and oxidation were measured. Myocardial nonesterified fatty acid in the DC rat model was significantly increased by 69%, while fatty acid transport protein-1, fatty acid transport proteins and fatty acidβ-oxidase were decreased by 68%,22% and 47%, respectively, when compared with the normal rats. Berberine at the dosage of 7.5, 15 and 30 mg/kg and Metformin 140 mg/kg treatment significant reduced myocardial NEFA by 34%,27% and 25% respectively, when compared with the rat model of DC. Meanwhile, Berberine 30 mg/kg treatment could significantly increase FATP-1, FATPs, and FA-β-oxidase by 159%,56% and 91%, when compared with the drug-untreated rat model.
Cardiac PPAR a, PPAR y and GLUT4 mRNA expression. Genes involved in cardiac glucose and lipid metabolism was evaluated by quantitative real-time PCR. As expected, cardiac mRNA expression of PPAR y and GLUT4 mRNA expression reduced by 38% and 34%, while PPAR a mRNA gene expression increased by 80% in the DC rat model, when compared with normal rats. Berberine 30 mg/kg treatment increase PPAR y and GLUT4 mRNA expression by 50% and 32%, and decreased PPAR a mRNA levels by 54% in the DC rat model, when compared with drug-untreated rat model.
Cardiac PPARα, PPAR y and GLUT4 protein expression. Protein expression of PPAR y and GLUT4 reduced by 40% and 68% respectively in the DC rat model, when compared with control rats. Berberine treatment significantly increased PPAR y and GLUT4 protein expression by 83% and 133% in the DC rat model, when compared with the drug-untreated rat model. However, berberine at the dosage of 30 mg/kg did not show any detectable changes in the cardiac PPAR a protein expression.
Conclusion
Phenotypes such as hyperglycemia, hypercholesterolemia, cardiac dysfunction and left ventricular hypertrophy, cardiac lipid accumulation, which mimics to the diabetic cardiomyopathy, were found in the rat model induced by high fat-high sucrose food plus streptozotocin treatment. Berberine treatment could effectively recover the diastolic and systolic dysfunction, inhibit the cardiac left ventricular hypertrophy, lower plasma sugar and lipids levels in the DC rat model. It could also alleviate cardiac lipid accumulation, increase intracellular fatty acid transport proteins and fatty acid beta-oxidase, and impressively increase mRNA and protein expression of PPAR y and GLUT4 and repress PPAR a gene expression, indicating a protective effect of berberine on experimental diabetic cardiomyopathy.
3. Inhibitory differentiation effect of berberine on 3T3-L1 fibroblasts
Objective
To study the effect of berberine on preadipocyte differentiation, lipid accumulation and adipokines secretory in the murine 3T3-L1 cell line.
Methods
Cell culture and treatments. Murine 3T3-L1 preadipocyte were grown on FALCON 6-well plates in a 5% CO2 atmosphere at 37℃and maintained in low glucose Dullbecco's Modified Eagle's medium supplemented with 10% fetal bovine serum,100 U/mL penicillin, and 100μg/mL streptomycin. The 2-day postconfluent 3T3-L1 cells (designed as Day 0) were incubated with 10% FBS/high glucose DMEM and antibiotics,500μM 3-isobutyl-1-methylxanthine, 1μM dexamethasone, and 5μg/ml insulin for 3 days (Day 0-2). Then the cells were incubated for 2 days in 10% FBS/HG-DMEM with insulin (Day 3-4), and, thereafter incubated in 10% FBS/HG-DMEM that was changed once every 2 days (Day 5-9). Cells receiving berberine chloride were given 10% FBS/HG-DMEM and insulin containing a final concentrantion of 5,10 and 20μM berberine in DMSO at Day 3 and Day4, then medium changed to only 10% FBS/HG-DMEM with berberine for last 5 days (Day 5-9).
Oil-Red-O staining. After differentiation (Day 9), cells were stained with Oil-Red-O to detect droplets in adipocytes. Cells were washed 3 times with phosphate buffered saline (PBS), fixed with 4% paraformaldehyde for 30 min and then stained with 1.8 mg/ml Oil-Red-O in 60% isopropanol for 30 min. Cells were washed with 60% isopropanol until colorless and observed under a microscope in PBS. Stained oil droplets in the cells were dissolved by Nonidet-P40 (4%, v/v, diluted in isopropanol) with gentle agitation for 5 min. Supernatant was measured with a spectrophotometer at 500 nm.
Reverse Transcription-Polymerase Chain Reaction. Total RNA was extracted from cultured 3T3-L1 adipocyte (Day 8) and preadipocyte by using QIAGEN RNeasy Mini Kit. Complementary DNA was generated from 2μg of total RNA and synthesized by using High Capacity cDNA Reverse Transcription Kit. The PCR conditions were as follows:for glyceraldehydes-3-phosphoate dehydrogenase (GAPDH) and adiponectin,25 cycles of 95℃for 30s,55℃for 30s,72℃for 30s; for resistin,27 cycles of 95℃for 30s,55℃for 30s,72℃for 30s; for peroxisome proliferator-activated receptor-y (PPAR y), adipocyte fatty acid binding protein (aP2), fatty acid synthase (FAS), angiotensinogen (AGT), monocyte chemoattractant protein 1 (MCP-1),28 cycles of 95℃for 30s,55℃for 30s,72℃for 30s; for CCAAT/enhancer binding protein (3 (C/EBP P), plasminogen activator inhibitor-1 (PAI-1),30 cycles of 95℃for 30s,55℃for 30s,72℃for 30s; for C/EBP a and leptin,31 cycles of 95℃for 30s,55℃for 30s,72℃for 30s. To allow for comparisons between samples and groups, quantities of all targets in test samples were normalized to GAPDH.
Results
Inhibitory effects of berberine on triglyceride content and lipid accumulation in 3T3-L1 cells. Berberine at the dosage of 5μM,10μM and 20μM significantly decreased triglyceride content (26%,37%, and 43%, respectively) and lipid accumulation of 3T3-L1 adipocyte in a dose-dependent manner.
Effects of berberine on transcription factors during differentiation process in 3T3-L1 cells. Berberine 10μM and 20μM significantly decreased C/EBP a (21% and 47%) and PPAR y mRNA (21% and 55%) gene expression in 3T3-L1 adipocyte in a dose dependent manner. Berberine at a dose of 20μM significantly reduced C/EBPβmRNA gene expression by 16%, whereas 5μM significantly increased C/EBP (3 mRNA gene expression by 21%.
Effects of berberine on expression of genes involved in lipid metabolism. Berberine at dosage of 10 and 20μM significantly decreased aP2 mRNA expression (18% and 40%). Berberine 20μM significantly reduced FAS mRNA expression by 18%, however, berberine 5μM significantly increased FAS gene expression by 15%.
Effects of berberine on adipokines (adiponectin, leptin, resistin, MCP-1, PAI-1 AGT) in 3T3-L1 cells. Berberine 5μM,10μM and 20μM significantly decreased adiponectin (9%,46% and 85%), leptin (33%,75% and 100%) and resistin (13%,63% and 82%) mRNA expression of 3T3-L1 cells in a dose dependent manner. Berberine 10μM and 20μM significantly decreased AGT mRNA expression (15% and 17%). Berberine in dose of 20μM caused significant reduction of PAI-1 (12%) and MCP-1 (28%) mRNA expression, whereas 5μM significantly increased PAI-1 (10%) and MCP-1 (26%) mRNA expression in 3T3-L1 adipocyte.
Conclusion
Berberine inhibited triglyceride and lipid accumulation in 3T3-L1 adipocyte. Berberine could inhibit differentiation of 3T3-L1 fibroblast via reducing transcription factors such as C/EBPβ, C/EBP a and PPAR y and their downstream genes aP2 and FAS. In term of inhibitory effect on differentiation in 3T3-L1 cells of berberine, adipokines including adiponectin, leptin, resistin, and AGT also showed significant decrease with berberine treatment, which might indicate anti-obesity action as well as cardiovascular protective effect of berberine. However, the reduction effect of berberine on MCP-1 and PAI-1 mRNA expression might be independent of differentiation inhibitory action.
引文
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