西洋参赤芍配伍对大鼠心肌梗死后早期心室重构心肌纤维化的影响
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摘要
目的观察益气活血配伍(西洋参茎叶总皂苷+赤芍总苷)对大鼠心肌梗死后早期心室重构炎性因子和心肌纤维化的影响,并从胶原代谢方面探讨可能的作用机制。方法结扎Wistar大鼠冠状动脉前降支制备AMI模型,将90只造模成功的大鼠随机分为6组,每组15只,分别为假手术组(冠状动脉前降支仅穿线不结扎)、模型组、阳性对照组(灌胃缬沙坦7.2 mg·kg~(-1)·d~(-1))、益气组(灌胃西洋参茎叶总皂苷162 mg·kg~(-1)·d~(-1))、活血组(灌胃赤芍总苷54 mg·kg~(-1)·d~(-1))和益气活血组(灌胃西洋参茎叶总皂苷162 mg·kg~(-1)·d~(-1)+赤芍总苷54mg·kg~(-1)·d~(-1))。第2天开始灌胃给药,连续4周,假手术组和模型组灌胃等量蒸馏水。4周后取材,超声心动图检测心脏结构及心功能变化,HE染色观察心肌组织病理变化,免疫组织化学染色法检测缺血心肌Ⅰ、Ⅲ型胶原蛋白的表达。放射性免疫法检测血清心肌损伤标记物B型脑钠尿肽(BNP)、肌钙蛋白T(cTnT),炎症因子肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β),纤维化指标层连蛋白(LA)、透明质酸(HA)、Ⅲ型前胶原氨基末端肽(PⅢNP)的含量。结果与模型组比较:(1)益气活血组大鼠心肌细胞炎性浸润减少,心肌纤维间隙水肿和心肌纤维细胞坏死变性明显减轻;(2)阳性对照组、活血组和益气活血组大鼠左室舒张末期内径(LVDd)均显著降低,左室射血分数(LVEF)均显著升高(P<0.05,P<0.05),益气活血组左室收缩末期内径(LVDs)显著降低(P<0.05);(3)阳性对照组和益气活血组心肌损伤标记物血清BNP水平明显降低(P<0.05);(4)阳性对照组和益气活血组炎性因子血清TNF-α、IL-1β含量显著降低(P<0.05,P<0.01);(5)益气活血组纤维化指标血清LA、HA、PⅢNP含量明显降低(P<0.05);(6)阳性对照组和益气活血组损伤心肌Ⅰ、Ⅲ型胶原蛋白表达明显降低(P<0.05,P<0.01)。结论益气活血配伍可以减轻心梗后心肌纤维化过程中的炎性反应,减少损伤心肌纤维化因子的释放及胶原的堆积从而达到减轻心室重构改善心功能的作用。
Objective To investigate the effect of the compatibility of supplementing qi and activating bloodcirculation(Panacis quinquefolii radix and Peoniae radix rubra) on inflammatory factor and myocardial fibrosisduring prophase ventricular remodeling(VR) after acute myocardial infarction(AMI) in rats and explore thepossible mechanism about collagen metabolism. Methods The AMI model was established by ligating the left anteriordescending coronary artery of Wistar rat to induce myocardial infarction. Ninety Wistar rats with model establishmentwere randomly divided into 6 groups, 15 rats in each group, including Sham group(the suture was penetratedaround the left anterior descending coronary artery,but not tied),model group,positive control group(PC) of which Valsartan was administered,supplementing qi(SQ) group of which Panas quinquefolium saponin was given,activating blood circulation(ABC) group of which total paeony glycosides was given, supplementing qi andactivating blood circulation(SQABC) group of which both Panas quinquefolium saponin and total paeony glycosideswere given. All of the medicine were given by gavage, both Sham group and model group were administered ofequivalent distilled water. After continuous intragastric administration of 4 weeks, ultrasonic cardiography wasconducted to examine the morphologic change and heart function. HE staining was used to observe the myocardialpathological change. Serum levels of B-type natriuretic peptide(BNP),cardiac troponin T(cTnT),inflammationfactors of tumor necrosis factor-alpha(TNF-α), interleukin-1β(IL-1β), myocardial fibrosis factors laminin(LN),hexadecenoic acid(HA),type Ⅲ procollagen(PⅢNP) were tested by radioimmunoassay method. Results Compared with model group:(1) Myocardial pathological changes of inflammatory infiltration in cardiac myocyte,edema in cardiac muscle fiber interspace and necrosis in myocardial fibrocyte obviously attenuated in SQABC group.(2) Ultrasonic cardiography detection showed that in PC group,ABC group,and SQABC group,1 eft ventricularend-diastole dimension reduced significantly, while left ventricular ejection fraction increased significantly(P<0.05, P<0.05). Left ventricular end-systole dimension reduced significantly in SQABC group(P<0.05).(3)The serum level of myocardial damage marker BNP obviously deceased in PC and SQABC group(P<0.05).(4)Serum levels of inflammation factors of TNF-α,IL-1β decreased significantly in PC and SQABC group(P<0.05,P<0.01);(5) Serum levels of myocardial fibrosis factors LN,HA,PⅢNP decreased significantly in SQABC group(P<0.05);(6) The myocardium protein expression of collagen Ⅰ and collagen Ⅲ decreased significantly in PCgroup and SQABC group(P<0.05, P<0.01). Conclusion The compatibility of supplementing qi and activatingblood circulation can alleviate the VR and improve heart function by alleviating the inflammation reaction in theprocess of myocardial fibrosis after AMI and reducing the release of myocardial fibrosis factors and accumulation ofcollagen.
Objective To investigate the effect of the compatibility of supplementing qi and activating bloodcirculation(Panacis quinquefolii radix and Peoniae radix rubra) on inflammatory factor and myocardial fibrosisduring prophase ventricular remodeling(VR) after acute myocardial infarction(AMI) in rats and explore thepossible mechanism about collagen metabolism. Methods The AMI model was established by ligating the left anteriordescending coronary artery of Wistar rat to induce myocardial infarction. Ninety Wistar rats with model establishmentwere randomly divided into 6 groups, 15 rats in each group, including Sham group(the suture was penetratedaround the left anterior descending coronary artery,but not tied),model group,positive control group(PC) of which Valsartan was administered,supplementing qi(SQ) group of which Panas quinquefolium saponin was given,activating blood circulation(ABC) group of which total paeony glycosides was given, supplementing qi andactivating blood circulation(SQABC) group of which both Panas quinquefolium saponin and total paeony glycosideswere given. All of the medicine were given by gavage, both Sham group and model group were administered ofequivalent distilled water. After continuous intragastric administration of 4 weeks, ultrasonic cardiography wasconducted to examine the morphologic change and heart function. HE staining was used to observe the myocardialpathological change. Serum levels of B-type natriuretic peptide(BNP),cardiac troponin T(cTnT),inflammationfactors of tumor necrosis factor-alpha(TNF-α), interleukin-1β(IL-1β), myocardial fibrosis factors laminin(LN),hexadecenoic acid(HA),type Ⅲ procollagen(PⅢNP) were tested by radioimmunoassay method. Results Compared with model group:(1) Myocardial pathological changes of inflammatory infiltration in cardiac myocyte,edema in cardiac muscle fiber interspace and necrosis in myocardial fibrocyte obviously attenuated in SQABC group.(2) Ultrasonic cardiography detection showed that in PC group,ABC group,and SQABC group,1 eft ventricularend-diastole dimension reduced significantly, while left ventricular ejection fraction increased significantly(P<0.05, P<0.05). Left ventricular end-systole dimension reduced significantly in SQABC group(P<0.05).(3)The serum level of myocardial damage marker BNP obviously deceased in PC and SQABC group(P<0.05).(4)Serum levels of inflammation factors of TNF-α,IL-1β decreased significantly in PC and SQABC group(P<0.05,P<0.01);(5) Serum levels of myocardial fibrosis factors LN,HA,PⅢNP decreased significantly in SQABC group(P<0.05);(6) The myocardium protein expression of collagen Ⅰ and collagen Ⅲ decreased significantly in PCgroup and SQABC group(P<0.05, P<0.01). Conclusion The compatibility of supplementing qi and activatingblood circulation can alleviate the VR and improve heart function by alleviating the inflammation reaction in theprocess of myocardial fibrosis after AMI and reducing the release of myocardial fibrosis factors and accumulation ofcollagen.
引文
[1]姚德山,张振刚,龚开政.心肌梗死后心肌纤维化的研究进展[J].中华临床医师杂志(电子版),2018,12(2):103-106.
[2] KOU-GI SHYU. The role of endoglin in myocardial fibrosis[J]. Acta Cardiol Sin. 2017,33(5):461-467
[3]石斌豪,徐宗佩,樊官伟.基于TGF-β1/Smads号通路治疗心肌梗死后心肌纤维化的研究进展[J].中国药理学通报,2018,34(1):5-8.
[4]张松飞,王晓娜,潘涛,等.中医药对心肌缺血再灌注损伤的保护作用及机制的实验研究进展[J].中国中医急症,2011,20(3):432-435.
[5]赵永锋,朱文晖,唐水娟,等.心梗后大鼠应变、应变率成像及心室重塑研究[J].中国超声医学杂志,2011,27(4):293-296.
[6]王承龙,史大卓,殷惠军,等.西洋参茎叶总皂苷对急性心肌梗死大鼠心肌VEGF、bFGF表达及血管新生的影响[J].中国中西医结合杂志,2007,27(4):331-334.
[7]张蕾,刘剑刚,张庆翔,等.心悦胶囊对大鼠心梗后缺血心肌骨桥蛋白和腱糖蛋白表达的影响[J].中国药理学通报,2013,29(12):1689-1695.
[8]吴修红,孙晓兰,胡妮娜,等.赤芍功效物质基础研究进展[J].中医药信息,2017,34(2):120-122.
[9]董国菊,刘剑刚,张庆祥,等.活血解毒中药组分配伍对急性心肌梗死后缺血心肌病理形态和心功能的影响[J].环球中医药,2015,8(11):1340,1345.
[10] SUNY,ZHANG J,LU L,et al. Tissue angiotensin II in the regulation of inflammatory and fibrogenic components of repair in the rat heart[J].J Lab Clin Med,2004,143:41-51.
[11] VILAHUR G, BABOTO J,PENA E,et al. Molecular and cellular mechanisms involved in cardiac remoeling after acute myocardial infarction[J]. J Mol Cell Cardiol,2011,50:522-533.
[12] FRANGOGIANNIS N G. Regulation of the inflammatory response in cardiac repair[J]. Circ Res,2012,110:159-173.
[13] MARCHANT D J, Boyd J H, Lin D C, et al. Inflammation in myocardial diseases[J]. Circ Res,2012,110:126-144.
[14] ROSE-JOHN S. IL-6 trans signaling via the soluble IL-6 receptor:importance for the pro-inflammatory activities of IL-6[J]. Int J Biol Sci,2012,8:1237-1247.
[15] ESPIRA L,MICHAEL P C. Emerging concepts in cardiac matrix biology[J]. Canadian journal of physiology and pharmacology,2009,87(12):996-1008.
[16]刘启寿,刘景群.充血性心力衰竭患者心肌纤维化变化的研究[J].中国当代医药,2014,21(31):42~43.
[17]沈雁,韦红,靳春兰.血府逐瘀汤对血管紧张素Ⅱ诱导的大鼠心肌成纤维细胞增殖及细胞外基质的影响[J].中西医结合学报,2011,9(3):313~319.
[18] MOSHAL K S, TYAGI N, MOSS V, et al. Early induction of matrix metalloproteinase-9 transducers signalling in human heart end stage failure[J]. J Cell Mol Med,2005,9(3):704-713.
[19] BJORNSTAD J L, SJAASTAD I, NYGARD S, et al. Collagen isoform shift during the early phase of reverse left ventricular remodelling after relief of pressure overload[J]. European Heart Journal,2011,32(2):236-245.
[20]李泽,孟哲,李宇娜,等.丹参酮ⅡA磺酸钠对血管紧张素Ⅱ诱导的大鼠心肌纤维化的影响[J].中国现代医学杂志,2018,28(12):17-23.
[21]黄会芳,霍新梅,霍丽娟,等.缬沙坦对肝纤维化大鼠瘦素、瘦素受体及Ⅰ型胶原表达的影响[J].中华肝脏病杂志,2018,26(2):119-124.
[22] SKOUMAL R, TOM M, SERPI R, et al. Parthenolide inhibits STAT3 signaling and attenuates angiotensin II-induced left ventricular hypertrophy via modulation of fibroblast activity[J]. J Mol Cell Cardial,2011,50(4):634-641.
[23] WEBER K T, SUN Y, Bhattacharya SK, et al. Myofibroblastmediated mechanisms of pathological remodelling of the heart[J].Nat Rev Cardiol,2013,10(1):15-26.
[2] KOU-GI SHYU. The role of endoglin in myocardial fibrosis[J]. Acta Cardiol Sin. 2017,33(5):461-467
[3]石斌豪,徐宗佩,樊官伟.基于TGF-β1/Smads号通路治疗心肌梗死后心肌纤维化的研究进展[J].中国药理学通报,2018,34(1):5-8.
[4]张松飞,王晓娜,潘涛,等.中医药对心肌缺血再灌注损伤的保护作用及机制的实验研究进展[J].中国中医急症,2011,20(3):432-435.
[5]赵永锋,朱文晖,唐水娟,等.心梗后大鼠应变、应变率成像及心室重塑研究[J].中国超声医学杂志,2011,27(4):293-296.
[6]王承龙,史大卓,殷惠军,等.西洋参茎叶总皂苷对急性心肌梗死大鼠心肌VEGF、bFGF表达及血管新生的影响[J].中国中西医结合杂志,2007,27(4):331-334.
[7]张蕾,刘剑刚,张庆翔,等.心悦胶囊对大鼠心梗后缺血心肌骨桥蛋白和腱糖蛋白表达的影响[J].中国药理学通报,2013,29(12):1689-1695.
[8]吴修红,孙晓兰,胡妮娜,等.赤芍功效物质基础研究进展[J].中医药信息,2017,34(2):120-122.
[9]董国菊,刘剑刚,张庆祥,等.活血解毒中药组分配伍对急性心肌梗死后缺血心肌病理形态和心功能的影响[J].环球中医药,2015,8(11):1340,1345.
[10] SUNY,ZHANG J,LU L,et al. Tissue angiotensin II in the regulation of inflammatory and fibrogenic components of repair in the rat heart[J].J Lab Clin Med,2004,143:41-51.
[11] VILAHUR G, BABOTO J,PENA E,et al. Molecular and cellular mechanisms involved in cardiac remoeling after acute myocardial infarction[J]. J Mol Cell Cardiol,2011,50:522-533.
[12] FRANGOGIANNIS N G. Regulation of the inflammatory response in cardiac repair[J]. Circ Res,2012,110:159-173.
[13] MARCHANT D J, Boyd J H, Lin D C, et al. Inflammation in myocardial diseases[J]. Circ Res,2012,110:126-144.
[14] ROSE-JOHN S. IL-6 trans signaling via the soluble IL-6 receptor:importance for the pro-inflammatory activities of IL-6[J]. Int J Biol Sci,2012,8:1237-1247.
[15] ESPIRA L,MICHAEL P C. Emerging concepts in cardiac matrix biology[J]. Canadian journal of physiology and pharmacology,2009,87(12):996-1008.
[16]刘启寿,刘景群.充血性心力衰竭患者心肌纤维化变化的研究[J].中国当代医药,2014,21(31):42~43.
[17]沈雁,韦红,靳春兰.血府逐瘀汤对血管紧张素Ⅱ诱导的大鼠心肌成纤维细胞增殖及细胞外基质的影响[J].中西医结合学报,2011,9(3):313~319.
[18] MOSHAL K S, TYAGI N, MOSS V, et al. Early induction of matrix metalloproteinase-9 transducers signalling in human heart end stage failure[J]. J Cell Mol Med,2005,9(3):704-713.
[19] BJORNSTAD J L, SJAASTAD I, NYGARD S, et al. Collagen isoform shift during the early phase of reverse left ventricular remodelling after relief of pressure overload[J]. European Heart Journal,2011,32(2):236-245.
[20]李泽,孟哲,李宇娜,等.丹参酮ⅡA磺酸钠对血管紧张素Ⅱ诱导的大鼠心肌纤维化的影响[J].中国现代医学杂志,2018,28(12):17-23.
[21]黄会芳,霍新梅,霍丽娟,等.缬沙坦对肝纤维化大鼠瘦素、瘦素受体及Ⅰ型胶原表达的影响[J].中华肝脏病杂志,2018,26(2):119-124.
[22] SKOUMAL R, TOM M, SERPI R, et al. Parthenolide inhibits STAT3 signaling and attenuates angiotensin II-induced left ventricular hypertrophy via modulation of fibroblast activity[J]. J Mol Cell Cardial,2011,50(4):634-641.
[23] WEBER K T, SUN Y, Bhattacharya SK, et al. Myofibroblastmediated mechanisms of pathological remodelling of the heart[J].Nat Rev Cardiol,2013,10(1):15-26.
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