辛伐他汀对糖尿病大鼠钙调蛋白及心功能不全的影响
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摘要
目的
研究辛伐他汀(simvastatin)对于链脲佐菌素(strepozotocin,STZ)致糖尿病大鼠心肌细胞内钙调蛋白、心脏血流动力学指标及血脂的影响,并就其机制做部分探讨。
实验方法
8周Sprague-Dawley(SD)大鼠随机分组为正常对照组(SD组)和糖尿病模型组(DM组),随后将造模成功大鼠(随机血糖＞16.7mmol/L)再随机分为辛伐他汀灌胃组(SIM组)及生理盐水灌胃组(DM)。共喂养3个月。后测定体重,予颈动脉插管行血流动力学检查,然后采集动脉血测定血脂浓度,并提取左心室组织,免疫印迹试验分析目标蛋白肌浆网Ca~(2+)-ATP酶、受磷蛋白表达,并测定各组间变化。
结果
1)链脲佐菌素60mg/dl腹腔注射建立糖尿病模型成功。
2)血流动力学指标:糖尿病+生理盐水(DM)组心室峰压(LVSP)、左心室内压上升最大速率(+dp/dtmax)和左心室内压下降最大速率(-dp/dtmax)显著低于糖尿病+辛伐他汀灌胃组(SIM)及SD组,左室舒张末压(LVEDP)显著高于SIM组及SD组(P＜0.05),而SIM组各项指标与SD组无显著统计学差异(DM SIM SD各组间:LVSP分别为83.3±10.0mmhg,104.3±14.9mmhg,114.2±14.9mmhg,LVEDP分别为14.5±3.7mmhg,6.7±4.6mmhg,4.4±4.0mmhg,+dp/dtmax分别为2151±454,4856±2281,5361±783,-dp/dtmax分别为2229±450,3465±1043,4263±801)
3)血脂:DM与SIM组间甘油三脂(TG)、总胆固醇(TC),低密度脂蛋白(LDL),高密度脂蛋白(HDL)无显著差异,但SD组TG、LDL显著低于SIM及DM组(P＜0.05),HDL显著高于SIM及DM组(P＜0.05),而TC较SIM及DM无显著差异。(DM SIM SD组间TG分别为116±49mg/dl,131±34 mg/dl,66±27mg/dl,TC分别为62±8 mg/dl,67±4.6 mg/dl,73±17 mg/dl,LDL分别为25±19 mg/dl,28±15.1 mg/dl,8±5 mg/dl,HDL分别为41±13 mg/dl,36±15 mg/dl,61±11 mg/dl)
4)目标蛋白表达:肌浆网Ca~(2+)-ATP酶(sarcoplasic reticulum Ca~(2+) -ATPase,SERCA2a)在SIM组表达高于DM组、而较SD组无明显差异,受磷蛋白(Phospholamban,PLB)在SIM组、DM组及SD组间表达无明显差异。
OBJECTIVE
To investigate the effect of simvastatin on myocardial calcium homeostasis, cardiac function,serum cholesterol level.
METHODS
Male 8-week-old Sprague-Dawley(SD) rats were divides into two groups.A group of rats was rendered diabetic with a single intraperitoneal injection streptozotocin in citrate buffer(Random blood glucose＞16.7mmol/L).Half of the rats with diabetes were kept with simvastatin,and the others were kept with 0.9%NS for up to 3 months.SD rats were used as normotensive controls.After 3 months,rats were anaesthetized and the arterial hemodynamic parameters were measured via a polyethylene tube filled with heparine/saline solution inserted into the right carotid artery.Left ventricular peak pressure(LVSP),left ventricular end-diastolic pressure(LVEDP),the maximal rate of rise and fall of pressure(+dp/dtmax and -dp/dtmax),as well as the concentrations of serum total cholesterol(TC),triglyceride(TG),HDL and LDL level were determined after the treatment.The protein expression of sarcoplasmic reticulum Ca~(2+-) ATPase (SERCA2a) and(phospholamban) PLB was also evaluated.
Results
Firstly,after simvastatin treatment,LVSP,+dp/dtmax,-dp/dtmax were significantly decreased,whereas LVEDP were remarkably increased in the DM group compared with SIM group(P＜0.05).However,no differences were found between SIM group and SD group.(DM SIM SD groups LVSP 83.3±10.0mmhg,104.3±14.9mmhg, 114.2±14.9mmhg,LVEDP 14.5±3.7mmhg,6.7±4.6mmhg,4.4±4.0mmhg, +dp/dtmax 2151±454,4856±1281,5361±783,-dp/dtmax 2229±450,3465±1043, 4263±801).
Secondly,serum concentrations of TC,TG,HDL,and LDL were no significant difference between DM and SIM groups.However,the level of TG and LDL in SD group is much lower and HDL is remarkably higher than in SIM and DM groups(P＜0.05),but the level of TC were no difference among three groups.(DM SIM SD groups TG 116±49mg/dl,131±34 mg/dl,66±27 mg/dl,TC 62±8 mg/dl, 67±4.6 mg/dl,73±17 mg/dl,LDL 25±19 mg/dl,28±15.1 mg/dl,8±5 mg/dl, HDL 41±13 mg/dl,36±15mg/dl,61±11mg/dl).
Furthermore,simvastatin prevented the decrease of SERCA2a,but showed no effect on PLB expression.These effects might be independent of its lipid-lowering effect.
研究辛伐他汀(simvastatin)对于链脲佐菌素(strepozotocin,STZ)致糖尿病大鼠心肌细胞内钙调蛋白、心脏血流动力学指标及血脂的影响,并就其机制做部分探讨。
实验方法
8周Sprague-Dawley(SD)大鼠随机分组为正常对照组(SD组)和糖尿病模型组(DM组),随后将造模成功大鼠(随机血糖＞16.7mmol/L)再随机分为辛伐他汀灌胃组(SIM组)及生理盐水灌胃组(DM)。共喂养3个月。后测定体重,予颈动脉插管行血流动力学检查,然后采集动脉血测定血脂浓度,并提取左心室组织,免疫印迹试验分析目标蛋白肌浆网Ca~(2+)-ATP酶、受磷蛋白表达,并测定各组间变化。
结果
1)链脲佐菌素60mg/dl腹腔注射建立糖尿病模型成功。
2)血流动力学指标:糖尿病+生理盐水(DM)组心室峰压(LVSP)、左心室内压上升最大速率(+dp/dtmax)和左心室内压下降最大速率(-dp/dtmax)显著低于糖尿病+辛伐他汀灌胃组(SIM)及SD组,左室舒张末压(LVEDP)显著高于SIM组及SD组(P＜0.05),而SIM组各项指标与SD组无显著统计学差异(DM SIM SD各组间:LVSP分别为83.3±10.0mmhg,104.3±14.9mmhg,114.2±14.9mmhg,LVEDP分别为14.5±3.7mmhg,6.7±4.6mmhg,4.4±4.0mmhg,+dp/dtmax分别为2151±454,4856±2281,5361±783,-dp/dtmax分别为2229±450,3465±1043,4263±801)
3)血脂:DM与SIM组间甘油三脂(TG)、总胆固醇(TC),低密度脂蛋白(LDL),高密度脂蛋白(HDL)无显著差异,但SD组TG、LDL显著低于SIM及DM组(P＜0.05),HDL显著高于SIM及DM组(P＜0.05),而TC较SIM及DM无显著差异。(DM SIM SD组间TG分别为116±49mg/dl,131±34 mg/dl,66±27mg/dl,TC分别为62±8 mg/dl,67±4.6 mg/dl,73±17 mg/dl,LDL分别为25±19 mg/dl,28±15.1 mg/dl,8±5 mg/dl,HDL分别为41±13 mg/dl,36±15 mg/dl,61±11 mg/dl)
4)目标蛋白表达:肌浆网Ca~(2+)-ATP酶(sarcoplasic reticulum Ca~(2+) -ATPase,SERCA2a)在SIM组表达高于DM组、而较SD组无明显差异,受磷蛋白(Phospholamban,PLB)在SIM组、DM组及SD组间表达无明显差异。
OBJECTIVE
To investigate the effect of simvastatin on myocardial calcium homeostasis, cardiac function,serum cholesterol level.
METHODS
Male 8-week-old Sprague-Dawley(SD) rats were divides into two groups.A group of rats was rendered diabetic with a single intraperitoneal injection streptozotocin in citrate buffer(Random blood glucose＞16.7mmol/L).Half of the rats with diabetes were kept with simvastatin,and the others were kept with 0.9%NS for up to 3 months.SD rats were used as normotensive controls.After 3 months,rats were anaesthetized and the arterial hemodynamic parameters were measured via a polyethylene tube filled with heparine/saline solution inserted into the right carotid artery.Left ventricular peak pressure(LVSP),left ventricular end-diastolic pressure(LVEDP),the maximal rate of rise and fall of pressure(+dp/dtmax and -dp/dtmax),as well as the concentrations of serum total cholesterol(TC),triglyceride(TG),HDL and LDL level were determined after the treatment.The protein expression of sarcoplasmic reticulum Ca~(2+-) ATPase (SERCA2a) and(phospholamban) PLB was also evaluated.
Results
Firstly,after simvastatin treatment,LVSP,+dp/dtmax,-dp/dtmax were significantly decreased,whereas LVEDP were remarkably increased in the DM group compared with SIM group(P＜0.05).However,no differences were found between SIM group and SD group.(DM SIM SD groups LVSP 83.3±10.0mmhg,104.3±14.9mmhg, 114.2±14.9mmhg,LVEDP 14.5±3.7mmhg,6.7±4.6mmhg,4.4±4.0mmhg, +dp/dtmax 2151±454,4856±1281,5361±783,-dp/dtmax 2229±450,3465±1043, 4263±801).
Secondly,serum concentrations of TC,TG,HDL,and LDL were no significant difference between DM and SIM groups.However,the level of TG and LDL in SD group is much lower and HDL is remarkably higher than in SIM and DM groups(P＜0.05),but the level of TC were no difference among three groups.(DM SIM SD groups TG 116±49mg/dl,131±34 mg/dl,66±27 mg/dl,TC 62±8 mg/dl, 67±4.6 mg/dl,73±17 mg/dl,LDL 25±19 mg/dl,28±15.1 mg/dl,8±5 mg/dl, HDL 41±13 mg/dl,36±15mg/dl,61±11mg/dl).
Furthermore,simvastatin prevented the decrease of SERCA2a,but showed no effect on PLB expression.These effects might be independent of its lipid-lowering effect.
引文
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