β受体阻滞剂对阿霉素心肌病小鼠的疗效观察及对嗜铬粒蛋白A表达的影响
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摘要
背景：慢性心力衰竭(chronic heart failure, CHF)是常见的临床综合征,伴有较高的发病率和致死率。β受体阻滞在治疗慢性心力衰竭中发挥有益作用。选择性β1受体阻滞剂美托洛尔和比索洛尔和非选择性β1受体阻滞剂卡维地络不仅能够改善心功能,还能降低慢性心力衰竭患者的致残率和致死率。但是,上述三种药物改善能力是否相同还有争议。在一项直接比较卡维地络和美托洛尔的临床试验中,卡维地络显示出了在改善生存率方面优于美托洛尔。美托洛尔、比索洛尔和卡维地络在治疗慢性心力衰竭有效性已经被广泛接受,但是现在还不明确这三种药物是否具有相同的疗效,还没有实验直接比较三种药物在慢性心力衰竭的作用及疗效。
嗜铬粒蛋白A(chromogranin A, CgA)是一个由439个氨基酸组成的分子量为49千道尔顿的可溶性酸性蛋白质,在神经内分泌系统中广泛存在并发挥作用。研究发现外周血CgA水平在慢性心力衰竭及心肌梗死后心力衰竭患者中明显升高,与心功能不全的严重程度相关,并且是慢性心力衰竭病人死亡的一个独立预测因子。目前己明确导致心力衰竭发生发展的基本机制是心肌重塑,而神经内分泌的过度激活在心肌重塑的发生发展中具有重要作用,心力衰竭患者交感神经的过度激活导致疾病的进展和不良的预后。许多学者认为外周循环的CgA水平可能代表了机体神经内分泌活性。而β受体阻滞剂能够降低交感神经张力,但β受体阻滞剂是否可影响CgA的表达,目前尚未探索。
本研究比较了卡维地络、美托洛尔和比索洛尔在慢性心力衰竭小鼠中的疗效以及三种药物对外周血及心肌CgA表达的影响。
第一部分小鼠阿霉素心肌病心力衰竭模型的建立
目的：探讨一种理想的建立小鼠阿霉素心肌病心力衰竭模型的方法。方法：20只C57BL/6小鼠和20只BALB/C小鼠分成四组。A组：C57BL/6(n=10),长期给药法；B组：C57BL/6(n=10),短期给药法；C组：BALB/C (n=10),短期给药法；D组：BALB/C (n=10),长期给药法。长期给药法：给予阿霉素2.0mg/kg腹腔注射,隔日一次,连续四次后改为一周一次,连续6周,总剂量为20mg/kg,总时间为8周；短期给药法：给予阿霉素2.5mg/kg腹腔注射,隔日一次连续6次,总剂量为15mg/kg,末次注射后再观察4周,总时间为6周。记录各组死亡的小鼠,实验前及结束时行心脏彩超检查。
结果：在长期给药方法中(A组和D组),在C57BL/6小鼠成功诱导心力衰竭模型,并且死亡率较低(10%),而BALB/C小鼠虽然也成功的建立了阿霉素心肌病模型,但是死亡率较高(70%),难以接受。在短期给药组(B组和C组),两组死亡率没有明显差异,但是BALB/C小鼠在注射前后EF和LVIDD没有明显变化,意味着建模的失败。而C57BL/6小鼠短期给药法死亡率与长期给药法无明显区别,建模后心脏射血分数及左心室舒张末内径无明显区别,同时节约了2周时间。
结论：C57BL/6小鼠比BALB/C小鼠更适合建立阿霉素心肌病心力衰竭模型,C57BL/6小鼠腹腔注射阿霉素,2.5mg/kg,隔日一次,连续6次,总量15mg/kg,连续观察4周是一种较为理想的建立阿霉素心肌病心力衰竭模型的方法。
第二部分不同β受体阻滞剂在心力衰竭小鼠中的疗效比较
目的：比较卡维地络、美托洛尔及比索洛尔对心力衰竭小鼠的疗效。
方法：82只C57BL/6小鼠中7只作为对照组(CON)。剩下的75只腹腔注射阿霉素(2.5mg/kg,隔日一次,连续6次,总剂量15mg/kg)建立阿霉素心肌病心力衰竭模型。成功建立模型的60只小鼠随机分为5组：卡维地络(CAR)、美托洛尔(MET)、培哚普利(PER)、比索洛尔(BIS)及阿霉素组(DOX)。CAR,卡维地络,靶剂量8mg/kg/d,每日分两次给予；MET,美托洛尔,靶剂量20mg/kg/d,每日分两次给予；PER,培哚普利,靶剂量1.5mg/kg/d,每日一次给予；BIS,比索洛尔,靶剂量1.5mg/kg/d,每日一次给予。以上4种药物均溶于羧甲基纤维素钠中,DOX和CON组小鼠给予羧甲基纤维素钠。6组小鼠分别给予上述药物灌胃,从小剂量开始,隔日增加一次剂量,4次后达到靶剂量,再维持6周。建模前、建模后及干预后分别行心脏超声检查,实验结束时经尾动脉测量血压及心率,心肌切片行心脏病理检查。
结果：DOX组2只小鼠死亡,其他组小鼠均存活。卡维地络、美托洛尔、比索洛尔在提高左心室射血分数,缩小左心室舒张末内径,减轻心肌病变程度具有相似的作用。
结论：卡维地络、美托洛尔、比索洛尔在慢性心力衰竭小鼠中疗效类似。
第三部分不同β受体阻滞剂对外周血及心肌嗜铬粒蛋白A表达的影响
目的：比较卡维地络、美托洛尔及比索洛尔对心力衰竭小鼠外周血及心肌嗜铬粒蛋白A表达的影响。
方法：动物模型同第二部分。实验结束前眼球取血用于ELISA检测外周血CgA的浓度,处死小鼠后截取心脏组织利用免疫组化及Western免疫印迹法检测心肌中CgA的表达。
结果：DOX组外周血及心肌CgA表达较CON组升高,卡维地络、美托洛尔、比索洛尔没有明显降低外周血CgA的表达,只有卡维地络减少了心肌CgA的表达。
结论：CgA尚不能作为慢性心力衰竭理想的标记物,不能根据其表达水平的变化来调整β受体阻滞剂的剂量。
Chronic heart failure is a common clinical syndrome with a high morbidity and mortality rate. Chronic beta-adrenergic receptor blockade is effective in treating heart failure. The beta-adrenergic receptor-selective blockers, metoprolol and bisoprolol, as well as carvedilol, a nonselective beta-adrenergic receptor antagonist with alpha1adrenergic receptor blocking and potent antioxidant activities, not only increase left ventricular systolic function but also reduce cardiac mortality and morbidity in patients with chronic heart failure. However, the extent of improvements produced by these agents varies. In a direct comparison study, carvedilol was shown to produce a greater survival benefit in patients with chronic heart failure when compared to metoprolol. There is broad consensus that these three drugs are effective in treating chronic heart failure. However, we do not know if one of them is superior to the others. There has not been a direct comparison of the three beta-blockers now widely used in clinical practice.
Chromogranin A (CgA) is a49-kDa protein with439amino acids, and it has been identified as playing a role in the endocrine and nervous systems. Circulating CgA has been shown to increase in proportion to clinical severity and to be associated with prognosis in patients with chronic or postinfarction heart failure. It has been widely accepted that ventricle remodeling plays an important part in the development of heart failure. The overactivation of neuroendocrine system plays a detrimental role in ventricle remodeling. The overactivation of the sympathetic nerves in chronic heart failure results in the progression of the disease and poor progonosis. Markedly elevated plasma levels of CgA have been observed in patients with neuroendocrine tumors. Many scientists believe that circulating CgA may integrate neuroendocrine signals from various sources and thus represent an index of overall neuroendocrine activity. If beta-blockers influence the expression of CgA in the circulation and myocardium, circulating CgA may be a good marker for heart failure and may be used to adjust beta-blocker doses to achieve the best beta-blockade.
In this study, we sought to explore the therapeutic effects of carvedilol, metoprolol and bisoprolol on doxorubicin-induced chronic heart failure in mice. Meanwhile, we examined their influence on the CgA expression in the myocardium and circulation.
PART1:The induction of chronic heart failure in mice
Objective:To develop an appropriate method to induce the model of chronic heart failure in mice with doxorubicin.
Methods:Twenty C57BL/6mice and twenty BALB/C mice were divided into four groups. GROUP A:C57BL/6(n=10), long-term method; GROUP B:C57BL/6(n=10), short-term method; GROUP C:BALB/C (n=10), short-term method; GROUP D: BALB/C (n=10), long-term method. The long-term method:doxorubicin2.0mg/kg, every other day for4times, then once a week for6times, for a total cumulative dose of20mg/kg, total time is8weeks; the short-term method:doxorubicin2.5mg/kg, every other day for6times for a total cumulative dose of15mg/kg, then observe for another4weeks after the last injection, total time is6weeks. Record every death of the mouse in each group. Echocardiography was done before and after the study. Results:In the long-term method groups (GROUP A and GROUP D), chronic heart failure was successfully induced in C57BL/6mice and with a low death rate (30%).Though BALB/C mice also presented with chronic heart failure, the death rate (70%) was too high to accept. In the short-term method groups (GROUP B and GROUP C), there is no significant difference in survival rate between GROUP B and GROUP C (90%vs80%). But there were no obvious changes in efection fraction and left ventricular internal diameter during diastole after the doxorubicin injection in BALB/C mice, which mean the failure to induce heart failure. As far as C57BL/6was concerned, the short term method shared similar death rate, ejection fraction and left ventricular internal diameter during diastole with the long term method. Meanwhile, the short term method saved2weeks than the long-term method. Conclusions:C57BL/6mice are more appropriate than BALB/C mice to be used to induce chronic heart failure with doxorubicin.Intraperitoneal injection of doxorubicin in C57BL/6mice (2.5mg/kg, every other day for6times for a total cumulative dose of15mg/kg, then another4weeks) is a reliable method to induce chronic heart failure.
PART2:Comparison of different beta-blockers on the therapeutic effects in chronic heart failure mice
Objective:To compare the therapeutic effects of carvedilol, metoprolol and bisoprolol in mice with chronic heart failure.
Methods:Seven mice were kept as controls (CON group) out of82C57BL/6mice. Seventy-five were injected intraperitoneally with doxorubicin,2.5mg/kg every other day6total times for a cumulative dose of15mg/kg. Before the first injection and4weeks after the last injection, echocardiography was performed to evaluate for systolic heart failure. Then, the mice with systolic heart failure were randomly assigned to one of the following groups:CAR, MET, PED, BIS and DOX. For the CAR group, carvedilol was administered twice a day at a target dose of8mg/kg/d. For the MET group, metoprolol was administered twice a day at a target dose of20mg/kg/d. For the PER group, perindopril was administered daily with a target dose of1.5mg/kg/d. For the BIS group, bisoprolol was administered daily with a target dose of1.5mg/kg/d. The DOX group did not receive any additional treatment. All drugs were dissolved in CMC (carboxymethyl cellulose) and administered intragastrically each day. The mice in the DOX and CON groups were given CMC daily. All drugs were initially given low doses, titrated to the target doses within a week, and then maintained at this dose for6weeks. At the end of the study, echocardiography, noninvasive measurement of the tail blood pressure and rate and histological analyses were done.
Results:Two mice in the DOX group died, the others survived. Carvedilol, metoprolol and bisoprolol shared the same ability in improving the left ventricle ejection fraction and decreasing the enlarged left ventricular internal diameter during diastole and ameliorating the extent of injury of the heart.
Conclusions:Our study suggests that carvedilol, metoprolol and bisoprolol share the same therapeutic ability.
PART3:Comparison of different beta-blockers on the expression of chromogranin A in chronic heart failure mice
Objective:To compare influences of carvedilol, metoprolol and bisoprolol on the expression of chromogranin A both in circulation and myocardium in mice with chronic heart failure.
Methods:Animal study was the same as was shown in the second part of the study. Serum chromogranin A (CgA) concentrations were detected by enzyme-linked immunosorbent assay. Myocardial expressions of CgA were detected by Immunohistochemistry and Western Blot.
Results:Although circulating CgA was elevated in heart failure mice, the three beta-blockers failed to lower it and circulating CgA failed to show a good correlation with ejection fraction. The myocardial expression of CgA was elevated about50%percent in the DOX group compared to the CON group. Carvedilol was the only drug among the four that was successful in lowering the myocardial expression of CgA.
Conclusion:Circulating CgA may not be a good marker for heart failure or the best choice in adjusting beta-blocker doses to achieve the best beta-blockade.
嗜铬粒蛋白A(chromogranin A, CgA)是一个由439个氨基酸组成的分子量为49千道尔顿的可溶性酸性蛋白质,在神经内分泌系统中广泛存在并发挥作用。研究发现外周血CgA水平在慢性心力衰竭及心肌梗死后心力衰竭患者中明显升高,与心功能不全的严重程度相关,并且是慢性心力衰竭病人死亡的一个独立预测因子。目前己明确导致心力衰竭发生发展的基本机制是心肌重塑,而神经内分泌的过度激活在心肌重塑的发生发展中具有重要作用,心力衰竭患者交感神经的过度激活导致疾病的进展和不良的预后。许多学者认为外周循环的CgA水平可能代表了机体神经内分泌活性。而β受体阻滞剂能够降低交感神经张力,但β受体阻滞剂是否可影响CgA的表达,目前尚未探索。
本研究比较了卡维地络、美托洛尔和比索洛尔在慢性心力衰竭小鼠中的疗效以及三种药物对外周血及心肌CgA表达的影响。
第一部分小鼠阿霉素心肌病心力衰竭模型的建立
目的：探讨一种理想的建立小鼠阿霉素心肌病心力衰竭模型的方法。方法：20只C57BL/6小鼠和20只BALB/C小鼠分成四组。A组：C57BL/6(n=10),长期给药法；B组：C57BL/6(n=10),短期给药法；C组：BALB/C (n=10),短期给药法；D组：BALB/C (n=10),长期给药法。长期给药法：给予阿霉素2.0mg/kg腹腔注射,隔日一次,连续四次后改为一周一次,连续6周,总剂量为20mg/kg,总时间为8周；短期给药法：给予阿霉素2.5mg/kg腹腔注射,隔日一次连续6次,总剂量为15mg/kg,末次注射后再观察4周,总时间为6周。记录各组死亡的小鼠,实验前及结束时行心脏彩超检查。
结果：在长期给药方法中(A组和D组),在C57BL/6小鼠成功诱导心力衰竭模型,并且死亡率较低(10%),而BALB/C小鼠虽然也成功的建立了阿霉素心肌病模型,但是死亡率较高(70%),难以接受。在短期给药组(B组和C组),两组死亡率没有明显差异,但是BALB/C小鼠在注射前后EF和LVIDD没有明显变化,意味着建模的失败。而C57BL/6小鼠短期给药法死亡率与长期给药法无明显区别,建模后心脏射血分数及左心室舒张末内径无明显区别,同时节约了2周时间。
结论：C57BL/6小鼠比BALB/C小鼠更适合建立阿霉素心肌病心力衰竭模型,C57BL/6小鼠腹腔注射阿霉素,2.5mg/kg,隔日一次,连续6次,总量15mg/kg,连续观察4周是一种较为理想的建立阿霉素心肌病心力衰竭模型的方法。
第二部分不同β受体阻滞剂在心力衰竭小鼠中的疗效比较
目的：比较卡维地络、美托洛尔及比索洛尔对心力衰竭小鼠的疗效。
方法：82只C57BL/6小鼠中7只作为对照组(CON)。剩下的75只腹腔注射阿霉素(2.5mg/kg,隔日一次,连续6次,总剂量15mg/kg)建立阿霉素心肌病心力衰竭模型。成功建立模型的60只小鼠随机分为5组：卡维地络(CAR)、美托洛尔(MET)、培哚普利(PER)、比索洛尔(BIS)及阿霉素组(DOX)。CAR,卡维地络,靶剂量8mg/kg/d,每日分两次给予；MET,美托洛尔,靶剂量20mg/kg/d,每日分两次给予；PER,培哚普利,靶剂量1.5mg/kg/d,每日一次给予；BIS,比索洛尔,靶剂量1.5mg/kg/d,每日一次给予。以上4种药物均溶于羧甲基纤维素钠中,DOX和CON组小鼠给予羧甲基纤维素钠。6组小鼠分别给予上述药物灌胃,从小剂量开始,隔日增加一次剂量,4次后达到靶剂量,再维持6周。建模前、建模后及干预后分别行心脏超声检查,实验结束时经尾动脉测量血压及心率,心肌切片行心脏病理检查。
结果：DOX组2只小鼠死亡,其他组小鼠均存活。卡维地络、美托洛尔、比索洛尔在提高左心室射血分数,缩小左心室舒张末内径,减轻心肌病变程度具有相似的作用。
结论：卡维地络、美托洛尔、比索洛尔在慢性心力衰竭小鼠中疗效类似。
第三部分不同β受体阻滞剂对外周血及心肌嗜铬粒蛋白A表达的影响
目的：比较卡维地络、美托洛尔及比索洛尔对心力衰竭小鼠外周血及心肌嗜铬粒蛋白A表达的影响。
方法：动物模型同第二部分。实验结束前眼球取血用于ELISA检测外周血CgA的浓度,处死小鼠后截取心脏组织利用免疫组化及Western免疫印迹法检测心肌中CgA的表达。
结果：DOX组外周血及心肌CgA表达较CON组升高,卡维地络、美托洛尔、比索洛尔没有明显降低外周血CgA的表达,只有卡维地络减少了心肌CgA的表达。
结论：CgA尚不能作为慢性心力衰竭理想的标记物,不能根据其表达水平的变化来调整β受体阻滞剂的剂量。
Chronic heart failure is a common clinical syndrome with a high morbidity and mortality rate. Chronic beta-adrenergic receptor blockade is effective in treating heart failure. The beta-adrenergic receptor-selective blockers, metoprolol and bisoprolol, as well as carvedilol, a nonselective beta-adrenergic receptor antagonist with alpha1adrenergic receptor blocking and potent antioxidant activities, not only increase left ventricular systolic function but also reduce cardiac mortality and morbidity in patients with chronic heart failure. However, the extent of improvements produced by these agents varies. In a direct comparison study, carvedilol was shown to produce a greater survival benefit in patients with chronic heart failure when compared to metoprolol. There is broad consensus that these three drugs are effective in treating chronic heart failure. However, we do not know if one of them is superior to the others. There has not been a direct comparison of the three beta-blockers now widely used in clinical practice.
Chromogranin A (CgA) is a49-kDa protein with439amino acids, and it has been identified as playing a role in the endocrine and nervous systems. Circulating CgA has been shown to increase in proportion to clinical severity and to be associated with prognosis in patients with chronic or postinfarction heart failure. It has been widely accepted that ventricle remodeling plays an important part in the development of heart failure. The overactivation of neuroendocrine system plays a detrimental role in ventricle remodeling. The overactivation of the sympathetic nerves in chronic heart failure results in the progression of the disease and poor progonosis. Markedly elevated plasma levels of CgA have been observed in patients with neuroendocrine tumors. Many scientists believe that circulating CgA may integrate neuroendocrine signals from various sources and thus represent an index of overall neuroendocrine activity. If beta-blockers influence the expression of CgA in the circulation and myocardium, circulating CgA may be a good marker for heart failure and may be used to adjust beta-blocker doses to achieve the best beta-blockade.
In this study, we sought to explore the therapeutic effects of carvedilol, metoprolol and bisoprolol on doxorubicin-induced chronic heart failure in mice. Meanwhile, we examined their influence on the CgA expression in the myocardium and circulation.
PART1:The induction of chronic heart failure in mice
Objective:To develop an appropriate method to induce the model of chronic heart failure in mice with doxorubicin.
Methods:Twenty C57BL/6mice and twenty BALB/C mice were divided into four groups. GROUP A:C57BL/6(n=10), long-term method; GROUP B:C57BL/6(n=10), short-term method; GROUP C:BALB/C (n=10), short-term method; GROUP D: BALB/C (n=10), long-term method. The long-term method:doxorubicin2.0mg/kg, every other day for4times, then once a week for6times, for a total cumulative dose of20mg/kg, total time is8weeks; the short-term method:doxorubicin2.5mg/kg, every other day for6times for a total cumulative dose of15mg/kg, then observe for another4weeks after the last injection, total time is6weeks. Record every death of the mouse in each group. Echocardiography was done before and after the study. Results:In the long-term method groups (GROUP A and GROUP D), chronic heart failure was successfully induced in C57BL/6mice and with a low death rate (30%).Though BALB/C mice also presented with chronic heart failure, the death rate (70%) was too high to accept. In the short-term method groups (GROUP B and GROUP C), there is no significant difference in survival rate between GROUP B and GROUP C (90%vs80%). But there were no obvious changes in efection fraction and left ventricular internal diameter during diastole after the doxorubicin injection in BALB/C mice, which mean the failure to induce heart failure. As far as C57BL/6was concerned, the short term method shared similar death rate, ejection fraction and left ventricular internal diameter during diastole with the long term method. Meanwhile, the short term method saved2weeks than the long-term method. Conclusions:C57BL/6mice are more appropriate than BALB/C mice to be used to induce chronic heart failure with doxorubicin.Intraperitoneal injection of doxorubicin in C57BL/6mice (2.5mg/kg, every other day for6times for a total cumulative dose of15mg/kg, then another4weeks) is a reliable method to induce chronic heart failure.
PART2:Comparison of different beta-blockers on the therapeutic effects in chronic heart failure mice
Objective:To compare the therapeutic effects of carvedilol, metoprolol and bisoprolol in mice with chronic heart failure.
Methods:Seven mice were kept as controls (CON group) out of82C57BL/6mice. Seventy-five were injected intraperitoneally with doxorubicin,2.5mg/kg every other day6total times for a cumulative dose of15mg/kg. Before the first injection and4weeks after the last injection, echocardiography was performed to evaluate for systolic heart failure. Then, the mice with systolic heart failure were randomly assigned to one of the following groups:CAR, MET, PED, BIS and DOX. For the CAR group, carvedilol was administered twice a day at a target dose of8mg/kg/d. For the MET group, metoprolol was administered twice a day at a target dose of20mg/kg/d. For the PER group, perindopril was administered daily with a target dose of1.5mg/kg/d. For the BIS group, bisoprolol was administered daily with a target dose of1.5mg/kg/d. The DOX group did not receive any additional treatment. All drugs were dissolved in CMC (carboxymethyl cellulose) and administered intragastrically each day. The mice in the DOX and CON groups were given CMC daily. All drugs were initially given low doses, titrated to the target doses within a week, and then maintained at this dose for6weeks. At the end of the study, echocardiography, noninvasive measurement of the tail blood pressure and rate and histological analyses were done.
Results:Two mice in the DOX group died, the others survived. Carvedilol, metoprolol and bisoprolol shared the same ability in improving the left ventricle ejection fraction and decreasing the enlarged left ventricular internal diameter during diastole and ameliorating the extent of injury of the heart.
Conclusions:Our study suggests that carvedilol, metoprolol and bisoprolol share the same therapeutic ability.
PART3:Comparison of different beta-blockers on the expression of chromogranin A in chronic heart failure mice
Objective:To compare influences of carvedilol, metoprolol and bisoprolol on the expression of chromogranin A both in circulation and myocardium in mice with chronic heart failure.
Methods:Animal study was the same as was shown in the second part of the study. Serum chromogranin A (CgA) concentrations were detected by enzyme-linked immunosorbent assay. Myocardial expressions of CgA were detected by Immunohistochemistry and Western Blot.
Results:Although circulating CgA was elevated in heart failure mice, the three beta-blockers failed to lower it and circulating CgA failed to show a good correlation with ejection fraction. The myocardial expression of CgA was elevated about50%percent in the DOX group compared to the CON group. Carvedilol was the only drug among the four that was successful in lowering the myocardial expression of CgA.
Conclusion:Circulating CgA may not be a good marker for heart failure or the best choice in adjusting beta-blocker doses to achieve the best beta-blockade.
引文
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