参葵通脉颗粒对慢性心力衰竭模型大鼠心肌超微结构及线粒体动力学的影响
|
摘要
目的探讨参葵通脉颗粒治疗慢性心力衰竭的可能作用机制。方法采用腹主动脉缩窄法制备慢性心力衰竭大鼠模型,40只造模成功大鼠随机分为模型组、阳性药组和中药低、中、高剂量组,每组8只,另以8只正常大鼠为假手术组。造模8周后,中药低、中、高剂量组分布给予参葵通脉颗粒4. 32、8. 64、17. 28 g/(kg·d)灌胃,阳性药组给予盐酸贝那普利片0. 9 mg/(kg·d)灌胃,假手术组和模型组给予蒸馏水10ml/(kg·d)灌胃。各组均灌胃4周后,检测各组大鼠心功能指标及血清血管紧张素Ⅱ(AngⅡ)水平,计算左心室指数(LVMI),电镜检测心肌超微结构,检测心肌组织动力相关蛋白1(Drp-1)、分裂蛋白1(Fis-1)、融合蛋白2(Mfn 2)、视神经萎缩蛋白1 (Opa 1)蛋白表达及腺苷酸活化蛋白激酶(AMPK)、过氧化物酶体增殖剂激活受体(PPARα) mRNA表达。结果与假手术组比较,模型组大鼠心功能及心肌超微结构损伤,血清AngⅡ水平升高,心肌组织Drp-1、Fis-1蛋白表达增加,Mfn 2、Opa 1蛋白表达及PPARαmRNA降低(P <0. 05)。与模型组比较,中药各剂量组上述指标均有一定程度改善,且以中药高剂量组效果最佳(P <0. 05)。结论参葵通脉颗粒对慢性心力衰竭模型大鼠心肌线粒体损伤有良好的改善作用,这可能是其治疗慢性心力衰竭的机制之一。
Objective To explore the probable mechanism of Shenkui Tongmai Granules(参葵通脉颗粒) in treating chronic heart failure. Methods Rat models of chronic cardiac failure were prepared by abdominal aortic coarctation. A total of 40 rats with successful modeling were randomly divided into model group,positive drug group and traditional Chinese medicine(TCM) low,medium and high dose groups,with 8 rats in each group. Another 8 normal rats were used as sham operation group. After 8 weeks of modeling,the low,medium and high doses of TCM groups were administered with 4. 32,8. 64,and 17. 28 g/(kg·d) Shenkui Tongmai Granules respectively,and the positive drug group was given 0. 9 mg/(kg · d) benazepril tablet for gavage administration. The sham operation group and model group were given 10 ml/(kg·d) distilled water. After 4 weeks of gavage,the cardiac function indexes and serum angiotensin Ⅱ(Ang Ⅱ) levels were measured in each group. The left ventricular index(LVMI) was calculated.The myocardial ultrastructure was detected by electron microscopy. The dynamin-related protein 1(Drp1),mitochondrial fission 1 protein(Fis-1),mitofusin 2(Mfn 2),optic atrophic protein 1(Opa 1) protein expression and adenosine monophosphate-activated protein kinase(AMPK),peroxisome proliferation agent activating receptor-α(PPARα) mRNA expression were detected. Results Compared with the sham operation group,the cardiac function and myocardial ultrastructural damage,serum AngⅡ level increased,myocardial tissue Drp-1 and Fis-1 protein expression increased,while Mfn 2,Opa 1 protein expression and PARα mRNA decreased in the model group(P <0. 05). Compared with the model group,the above-mentioned indicators of high,medium and low dose TCM groups improved,and the effect was best in the high TCM dose group(P < 0. 05). Conclusion Shenkui Tongmai Granules can improve the myocardial mitochondrial damage in rats with chronic heart failure,which may be one of the mechanisms for the treatment of chronic cardiac failure.
Objective To explore the probable mechanism of Shenkui Tongmai Granules(参葵通脉颗粒) in treating chronic heart failure. Methods Rat models of chronic cardiac failure were prepared by abdominal aortic coarctation. A total of 40 rats with successful modeling were randomly divided into model group,positive drug group and traditional Chinese medicine(TCM) low,medium and high dose groups,with 8 rats in each group. Another 8 normal rats were used as sham operation group. After 8 weeks of modeling,the low,medium and high doses of TCM groups were administered with 4. 32,8. 64,and 17. 28 g/(kg·d) Shenkui Tongmai Granules respectively,and the positive drug group was given 0. 9 mg/(kg · d) benazepril tablet for gavage administration. The sham operation group and model group were given 10 ml/(kg·d) distilled water. After 4 weeks of gavage,the cardiac function indexes and serum angiotensin Ⅱ(Ang Ⅱ) levels were measured in each group. The left ventricular index(LVMI) was calculated.The myocardial ultrastructure was detected by electron microscopy. The dynamin-related protein 1(Drp1),mitochondrial fission 1 protein(Fis-1),mitofusin 2(Mfn 2),optic atrophic protein 1(Opa 1) protein expression and adenosine monophosphate-activated protein kinase(AMPK),peroxisome proliferation agent activating receptor-α(PPARα) mRNA expression were detected. Results Compared with the sham operation group,the cardiac function and myocardial ultrastructural damage,serum AngⅡ level increased,myocardial tissue Drp-1 and Fis-1 protein expression increased,while Mfn 2,Opa 1 protein expression and PARα mRNA decreased in the model group(P <0. 05). Compared with the model group,the above-mentioned indicators of high,medium and low dose TCM groups improved,and the effect was best in the high TCM dose group(P < 0. 05). Conclusion Shenkui Tongmai Granules can improve the myocardial mitochondrial damage in rats with chronic heart failure,which may be one of the mechanisms for the treatment of chronic cardiac failure.
引文
[1]SHIMOKAWA H,MIURA M,NOCHIOKA K,et al.Heart failure as a general pandemic in Asia[J]. Eur J Heart Fail,2015,17(9):884-892.
[2]GEDELA M,KHAN M,JONSSON O. Heart failure[J].S D Med,2015,68(9):403-405,407-409.
[3]SUN J,ZHANG K,XIONG WJ,et al. Clinical effects of a standardized Chinese herbal remedy,Qili Qiangxin,as an adjuvant treatment in heart failure:systematic review and meta-analysis[J]. BMC Complement Altern Med,2016,16:201. doi:10. 1186/s12906-016-1174-1.
[4]严士海,王道成,沈竹阳,等.参葵通脉颗粒治疗慢性心力衰竭气虚血瘀证310例临床观察[J].中医杂志,2018,59(4):316-319.
[5]苗梦露,李七一,严士海,等.抗心衰颗粒对心衰大鼠RAAS及心肌细胞内TGF-β1的影响[J].南京中医药大学学报,2013,29(3):247-250.
[6]朱林强,周永焯,谢晓明,等.大鼠腹主动脉缩窄术致大鼠慢性心衰的建模与体会[J].现代医院,2015,15(10):21-24.
[7]周仲瑛.读经典,谈感悟[J].南京中医药大学学报,1997,23(5):273-277.
[8]LIANG T,ZHANG Y,YIN S,et al. Cardio-protecteffect of qiliqiangxin capsule on left ventricular remodeling,dysfunction and apoptosis in heart failure rats after chronic myocardial infarction[J]. Am J Transl Res,2016,8(5):2047-2058.
[9]ZHANG K,ZHOU Q,GUO Y,et al. Mitochondria-associated endoplasmic reticulum membranes(MAMs)involve in the regulation of mitochondrial dysfunction and heart failure[J]. Acta Biochim Biophys Sin(Shanghai),2018,50(6):618-619.
[10]NAN J,ZHU W,RAHMAN MS,et al. Molecular regulation of mitochondrial dynamics in cardiac disease[J].Biochim Biophys Acta,2017,1864(7):1260-1273.
[11]RIBA A,DERES L,EROS K,et al. Doxycycline protects against ROS-induced mitochondrial fragmentation and ISO-induced heart failure[J]. PLo S One,2017,12(4):e0175195.
[12]GIVVIMANI S,PUSHPAKUMAR S,VEERANKI S,et al. Dysregulation of Mfn2 and Drp-1 proteins in heart failure[J]. Can J Physiol Pharmacol,2014,92(7):583-591.
[13]GIVVIMANI S,PUSHPAKUMAR SB,METREVELI N,et al. Role of mitochondrial fission and fusion in cardiomyocyte contractility[J]. Int J Cardiol,2015,187:325-333. doi:10. 1016/j. ijcard. 2015. 03. 352.
[14]FENG Y,ZHANG Y,XIAO H. AMPK and cardiac remodelling[J]. Sci China Life Sci,2018,61(1):14-23.
[15]赛庆彬,马延超,朱荣.有氧运动抑制心力衰竭大鼠心脏脂质沉积:AMPK-PPARα信号通路的作用[J].中国运动医学杂志,2012,31(12):1081-1086.
[2]GEDELA M,KHAN M,JONSSON O. Heart failure[J].S D Med,2015,68(9):403-405,407-409.
[3]SUN J,ZHANG K,XIONG WJ,et al. Clinical effects of a standardized Chinese herbal remedy,Qili Qiangxin,as an adjuvant treatment in heart failure:systematic review and meta-analysis[J]. BMC Complement Altern Med,2016,16:201. doi:10. 1186/s12906-016-1174-1.
[4]严士海,王道成,沈竹阳,等.参葵通脉颗粒治疗慢性心力衰竭气虚血瘀证310例临床观察[J].中医杂志,2018,59(4):316-319.
[5]苗梦露,李七一,严士海,等.抗心衰颗粒对心衰大鼠RAAS及心肌细胞内TGF-β1的影响[J].南京中医药大学学报,2013,29(3):247-250.
[6]朱林强,周永焯,谢晓明,等.大鼠腹主动脉缩窄术致大鼠慢性心衰的建模与体会[J].现代医院,2015,15(10):21-24.
[7]周仲瑛.读经典,谈感悟[J].南京中医药大学学报,1997,23(5):273-277.
[8]LIANG T,ZHANG Y,YIN S,et al. Cardio-protecteffect of qiliqiangxin capsule on left ventricular remodeling,dysfunction and apoptosis in heart failure rats after chronic myocardial infarction[J]. Am J Transl Res,2016,8(5):2047-2058.
[9]ZHANG K,ZHOU Q,GUO Y,et al. Mitochondria-associated endoplasmic reticulum membranes(MAMs)involve in the regulation of mitochondrial dysfunction and heart failure[J]. Acta Biochim Biophys Sin(Shanghai),2018,50(6):618-619.
[10]NAN J,ZHU W,RAHMAN MS,et al. Molecular regulation of mitochondrial dynamics in cardiac disease[J].Biochim Biophys Acta,2017,1864(7):1260-1273.
[11]RIBA A,DERES L,EROS K,et al. Doxycycline protects against ROS-induced mitochondrial fragmentation and ISO-induced heart failure[J]. PLo S One,2017,12(4):e0175195.
[12]GIVVIMANI S,PUSHPAKUMAR S,VEERANKI S,et al. Dysregulation of Mfn2 and Drp-1 proteins in heart failure[J]. Can J Physiol Pharmacol,2014,92(7):583-591.
[13]GIVVIMANI S,PUSHPAKUMAR SB,METREVELI N,et al. Role of mitochondrial fission and fusion in cardiomyocyte contractility[J]. Int J Cardiol,2015,187:325-333. doi:10. 1016/j. ijcard. 2015. 03. 352.
[14]FENG Y,ZHANG Y,XIAO H. AMPK and cardiac remodelling[J]. Sci China Life Sci,2018,61(1):14-23.
[15]赛庆彬,马延超,朱荣.有氧运动抑制心力衰竭大鼠心脏脂质沉积:AMPK-PPARα信号通路的作用[J].中国运动医学杂志,2012,31(12):1081-1086.