温阳益心活血化痰法对缺血心肌血管新生作用及机制研究
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摘要
1.研究背景
治疗性血管新生在冠心病中的应用被形象地称为:“药物促进的心脏自身搭桥”,目前已成为一个新的研究热点。本研究即以温阳益心活血化痰法为切入点,在全面总结治疗性血管新生文献的基础上,通过对该法治疗冠心病的理论探讨,立足于临床实践,运用先进的实验方法,研究该法对冠心病缺血心肌血管新生的作用及作用机制,以期为中医药治疗冠心病提供新的理论与思路,并为中医药治疗性血管新生在冠心病方面的应用提供一个理论与实验研究的技术平台。
2.研究方法
2.1基于临床实践的温阳益心活血化痰法治疗冠心病的理论探讨
收集2006年3月—2007年12月导师曹洪欣教授诊治冠心病的医案124例,建立相应数据库,通过现代中医知识网络与中医自然语言理解技术、小样本数据挖掘与可视化技术,挖掘导师用温阳益心活血化痰法治疗冠心病的临床经验。
2.2温阳益心活血化痰法对缺血心肌血管新生的实验研究
制备鸡胚尿囊膜(CAM)模型及结扎大鼠心脏左前降支动脉所致急性心肌梗死模型,用光镜、透射电镜、免疫组化、实时荧光PCR、图像处理等技术,观察CAM新生血管数、心肌梗死面积、梗死边缘区血管面密度、AMI大鼠心肌的病理及超微结构的变化、梗死边缘区VEGF、bFGF蛋白及其mRNA的表达等,研究温阳益心活血化痰法对CAM及实验性心肌梗死大鼠心脏的促血管新生作用及机制。
3.研究结果
3.1基于临床病例的温阳益心活血化痰法治疗冠心病的研究
冠心病的辨证分型中,受关注度最高的前两位是心阳虚证和痰瘀互阻证;在用药中,几乎每一个病例都用到温性药物,温性用药关注度最高为1;药物归经中以归肺、心、脾经较多;药物规律分析中,挖掘出导师擅用经方,以瓜蒌薤白半夏汤为基础,或加茯苓健脾利湿,或加赤芍、川芎以活血行气,痰瘀同治为主要的治法,参类与桂枝、薤白也是常用药,又体现了“补中寓通、补有利通、通补兼施”的特点,并由此确立了温阳益心活血化痰法治疗冠心病的学术思想及此思想指导下的温心方:生晒参10g、桂枝10g、瓜蒌15g、薤白15g、半夏10g、川连6g、赤芍15g、川芎15g、麦冬10g、生龙骨30g、甘草10g等。
3.2温阳益心活血化痰法对缺血心肌血管新生的实验研究
3.2.1温心方对CAM血管生成有明显的促进作用,与模型组比较统计学有显著性差异(P＜0.01);
3.2.2温心方能显著减少心肌梗死面积,增加梗死边缘区的血管面密度(MVD),与模型组相比有显著性差异((P＜0.01),其作用随药物剂量增加而有加强趋势;
3.2.3温心方能显著增加梗死心肌边缘区VEGF、bFGF的蛋白表达,与模型组相比统计学有显著性差异(P＜0.01-P＜0.05),但大、小剂量组组间比较无统计学差异((P＞0.05);
3.2.4温心方能显著增加梗死心肌边缘区VEGFmRNA、bFGFmRNA的表达,与模型组相比统计学有显著性差异(P＜0.01-P＜0.05)。
4.结论
4.1心阳虚是胸痹发病的主要病理基础,痰浊、血瘀是胸痹发病的主要病理因素,温阳益心活血化痰法是治疗冠心病的有效方法。
4.2“通”之含义有二:一使原有不通的心脉得以畅通,二使不通的血脉周围形成新的血脉,以发挥正常渗灌血液的作用。
4.3温阳益心活血化痰法对鸡胚尿囊膜及大鼠AMI模型的血管生成均具有一定促进作用。
4.4温阳益心活血化痰法促血管新生的作用机制可能是通过上调VEGF、bFGF蛋白及基因表达而实现的。
1.Background:
It is believed that therapeutic angiogenesis has been called a drug promoting self heart bypass grafting in the treatment of coronary heart disease(CHD).And it has been a new hotspot in the cardiovascular research field.This study is based on the research of yang warming,heart nourishment, blood activation and phlegm clearing and the comprehensively summarizing the papers which are about angiogenesis,through the theoretical study of this method and clinical practice and adapting some advanced experimental techniques,we study the effcet and mechanisms of WRAE in angiogenesis,and our purpose is to provide some theories and thinkings of TCM in treating CHD,and provide a technological platform of TCM therapeutic angiogenesis in treating CHD.
2.Research method
2.1Theoretical studies on patients with CHD using yang warming,heart nourishment,blood activation and phlegm clearing therapies based on clinical practice
With the collection of medical documents of 124 CHD cases who have been treated by Pro.Cao Hongxin at the outpatient department of China ACHDemy of Chinese Medical Science from Mar.2006 to Dec.2007,we have deeply unearthed his clinical experiences through knowledge networks of modern Chinese medicine,understanding techniques of natural linguistics in Chinese medicine,small sample data unearthing and visualization techniques.
2.2 The experimental study of WRAE method on angiogenesis in ischemic heart myocardium
The CAM model and myocardium infarction rats model were established.The research was to observe effect and mechanisms on angiogenesis of WRAE method.The results are based on different indexes such as:the numbers of regenerated vessels,areas in the infarction positions,spacial distribution in myocardium capilaries,changes of myocardium ultrastruture under the microscope and electron microscope.
3.Results
3.1 Clinical studies on patients with CHD using yang warming,heart nourishment,blood activation and phlegm clearing therapies
The result turns out that during the syndrome differentiation of CHD, inter-obstruction of phlegm and stagnation,heart yang insufficiency are the top two most focused syndromes.In herbal prescription,herbs with warm properties are used in almost all cases.Most of the drugs selected are from lung,heart,spleen meridians.During the analysis of regularities of herb prescription,it is apparent that my mentor is good at classical prescription using herbs based on gualouxiebaibaixia decoction,or with addition of fulin to invigorate the spleen and drain dampness,or with addition of chishao, chuanxiong to activate blood and improve qi circulation,or with concomitant treatment targeting both phlegm and stagnation.In addition,ginseng group herbs,guizhi and xiebai are also commonly used;it embodies the acdemic thought of "dredging based on enrichment".According to these,acdemic thoughts of treatment of CHD using yang warming,heart nourishment,blood activation and phlegm clearing are established and wenxin capsule which is made of shengshaishen,guizhi gualou,xiebai is produced from this theory.
3.2 The experimental study of WRAE method on angiogenesis in ischemic heart myocardium
3.2.1 wenxin capsule group has the promoting effect on angiogenesis in CAM, the significant difference can be found between the therapeutic group and model group as well as normal serum group(P＜0.01-0.05).
3.2.2 Wenxin capsule could obviously decrease the areas of infarcted myocardium,Wenxin capsule could obviously increase the MVD in the margins of infarcted area,the significant difference can be found compared to the model group(P＜0.01).And this effect can be enhanced in a dose-dependent manner.
3.2.3 The protein levels of VEGF,bFGF are increased in the margin of infarcted areas in the two different dosage groups,the difference is significant compared to the model group(P＜0.01-P＜0.05),but no significant difference was found between the two dosage groups themselves
3.2.4 Wenxin capsule high group could obviously inrease the expression of VEGF,bFGFmRNA in the margins of infarcted areas,the difference is significant compared to the model group(P＜0.01-0.05) and no significant difference was found between high dosage group and possitive control group(P＞0.05).
4.Conclusion
4.1 Heart yang insufficiency is the main part of its pathological basis,and phlegm and turbid fluid as well as blood stasis are the major pathological factors.The method of yang warming,heart nourishment,blood activation and phlegm clearing is the effective therapeutic method in the treatment of CHD.
4.2 The word "dredging" has double indications:first,it is to dredge the obstructed heart meridian;second,it is to facilitate vessel regensis around the former obstructed vessels to help local tissue regain blood perfusion.
4.3 WRAE theory has a certain promoting effect on angiogenesis in both CAM and AMI rats models.
4.4 The mechanisms of WRAE theory in promoting angiogenesis may be related to its upregulating the expression levels of the proteins and mRNA of VEGF,bFGF in the margins of infarcted mycardium.
治疗性血管新生在冠心病中的应用被形象地称为:“药物促进的心脏自身搭桥”,目前已成为一个新的研究热点。本研究即以温阳益心活血化痰法为切入点,在全面总结治疗性血管新生文献的基础上,通过对该法治疗冠心病的理论探讨,立足于临床实践,运用先进的实验方法,研究该法对冠心病缺血心肌血管新生的作用及作用机制,以期为中医药治疗冠心病提供新的理论与思路,并为中医药治疗性血管新生在冠心病方面的应用提供一个理论与实验研究的技术平台。
2.研究方法
2.1基于临床实践的温阳益心活血化痰法治疗冠心病的理论探讨
收集2006年3月—2007年12月导师曹洪欣教授诊治冠心病的医案124例,建立相应数据库,通过现代中医知识网络与中医自然语言理解技术、小样本数据挖掘与可视化技术,挖掘导师用温阳益心活血化痰法治疗冠心病的临床经验。
2.2温阳益心活血化痰法对缺血心肌血管新生的实验研究
制备鸡胚尿囊膜(CAM)模型及结扎大鼠心脏左前降支动脉所致急性心肌梗死模型,用光镜、透射电镜、免疫组化、实时荧光PCR、图像处理等技术,观察CAM新生血管数、心肌梗死面积、梗死边缘区血管面密度、AMI大鼠心肌的病理及超微结构的变化、梗死边缘区VEGF、bFGF蛋白及其mRNA的表达等,研究温阳益心活血化痰法对CAM及实验性心肌梗死大鼠心脏的促血管新生作用及机制。
3.研究结果
3.1基于临床病例的温阳益心活血化痰法治疗冠心病的研究
冠心病的辨证分型中,受关注度最高的前两位是心阳虚证和痰瘀互阻证;在用药中,几乎每一个病例都用到温性药物,温性用药关注度最高为1;药物归经中以归肺、心、脾经较多;药物规律分析中,挖掘出导师擅用经方,以瓜蒌薤白半夏汤为基础,或加茯苓健脾利湿,或加赤芍、川芎以活血行气,痰瘀同治为主要的治法,参类与桂枝、薤白也是常用药,又体现了“补中寓通、补有利通、通补兼施”的特点,并由此确立了温阳益心活血化痰法治疗冠心病的学术思想及此思想指导下的温心方:生晒参10g、桂枝10g、瓜蒌15g、薤白15g、半夏10g、川连6g、赤芍15g、川芎15g、麦冬10g、生龙骨30g、甘草10g等。
3.2温阳益心活血化痰法对缺血心肌血管新生的实验研究
3.2.1温心方对CAM血管生成有明显的促进作用,与模型组比较统计学有显著性差异(P＜0.01);
3.2.2温心方能显著减少心肌梗死面积,增加梗死边缘区的血管面密度(MVD),与模型组相比有显著性差异((P＜0.01),其作用随药物剂量增加而有加强趋势;
3.2.3温心方能显著增加梗死心肌边缘区VEGF、bFGF的蛋白表达,与模型组相比统计学有显著性差异(P＜0.01-P＜0.05),但大、小剂量组组间比较无统计学差异((P＞0.05);
3.2.4温心方能显著增加梗死心肌边缘区VEGFmRNA、bFGFmRNA的表达,与模型组相比统计学有显著性差异(P＜0.01-P＜0.05)。
4.结论
4.1心阳虚是胸痹发病的主要病理基础,痰浊、血瘀是胸痹发病的主要病理因素,温阳益心活血化痰法是治疗冠心病的有效方法。
4.2“通”之含义有二:一使原有不通的心脉得以畅通,二使不通的血脉周围形成新的血脉,以发挥正常渗灌血液的作用。
4.3温阳益心活血化痰法对鸡胚尿囊膜及大鼠AMI模型的血管生成均具有一定促进作用。
4.4温阳益心活血化痰法促血管新生的作用机制可能是通过上调VEGF、bFGF蛋白及基因表达而实现的。
1.Background:
It is believed that therapeutic angiogenesis has been called a drug promoting self heart bypass grafting in the treatment of coronary heart disease(CHD).And it has been a new hotspot in the cardiovascular research field.This study is based on the research of yang warming,heart nourishment, blood activation and phlegm clearing and the comprehensively summarizing the papers which are about angiogenesis,through the theoretical study of this method and clinical practice and adapting some advanced experimental techniques,we study the effcet and mechanisms of WRAE in angiogenesis,and our purpose is to provide some theories and thinkings of TCM in treating CHD,and provide a technological platform of TCM therapeutic angiogenesis in treating CHD.
2.Research method
2.1Theoretical studies on patients with CHD using yang warming,heart nourishment,blood activation and phlegm clearing therapies based on clinical practice
With the collection of medical documents of 124 CHD cases who have been treated by Pro.Cao Hongxin at the outpatient department of China ACHDemy of Chinese Medical Science from Mar.2006 to Dec.2007,we have deeply unearthed his clinical experiences through knowledge networks of modern Chinese medicine,understanding techniques of natural linguistics in Chinese medicine,small sample data unearthing and visualization techniques.
2.2 The experimental study of WRAE method on angiogenesis in ischemic heart myocardium
The CAM model and myocardium infarction rats model were established.The research was to observe effect and mechanisms on angiogenesis of WRAE method.The results are based on different indexes such as:the numbers of regenerated vessels,areas in the infarction positions,spacial distribution in myocardium capilaries,changes of myocardium ultrastruture under the microscope and electron microscope.
3.Results
3.1 Clinical studies on patients with CHD using yang warming,heart nourishment,blood activation and phlegm clearing therapies
The result turns out that during the syndrome differentiation of CHD, inter-obstruction of phlegm and stagnation,heart yang insufficiency are the top two most focused syndromes.In herbal prescription,herbs with warm properties are used in almost all cases.Most of the drugs selected are from lung,heart,spleen meridians.During the analysis of regularities of herb prescription,it is apparent that my mentor is good at classical prescription using herbs based on gualouxiebaibaixia decoction,or with addition of fulin to invigorate the spleen and drain dampness,or with addition of chishao, chuanxiong to activate blood and improve qi circulation,or with concomitant treatment targeting both phlegm and stagnation.In addition,ginseng group herbs,guizhi and xiebai are also commonly used;it embodies the acdemic thought of "dredging based on enrichment".According to these,acdemic thoughts of treatment of CHD using yang warming,heart nourishment,blood activation and phlegm clearing are established and wenxin capsule which is made of shengshaishen,guizhi gualou,xiebai is produced from this theory.
3.2 The experimental study of WRAE method on angiogenesis in ischemic heart myocardium
3.2.1 wenxin capsule group has the promoting effect on angiogenesis in CAM, the significant difference can be found between the therapeutic group and model group as well as normal serum group(P＜0.01-0.05).
3.2.2 Wenxin capsule could obviously decrease the areas of infarcted myocardium,Wenxin capsule could obviously increase the MVD in the margins of infarcted area,the significant difference can be found compared to the model group(P＜0.01).And this effect can be enhanced in a dose-dependent manner.
3.2.3 The protein levels of VEGF,bFGF are increased in the margin of infarcted areas in the two different dosage groups,the difference is significant compared to the model group(P＜0.01-P＜0.05),but no significant difference was found between the two dosage groups themselves
3.2.4 Wenxin capsule high group could obviously inrease the expression of VEGF,bFGFmRNA in the margins of infarcted areas,the difference is significant compared to the model group(P＜0.01-0.05) and no significant difference was found between high dosage group and possitive control group(P＞0.05).
4.Conclusion
4.1 Heart yang insufficiency is the main part of its pathological basis,and phlegm and turbid fluid as well as blood stasis are the major pathological factors.The method of yang warming,heart nourishment,blood activation and phlegm clearing is the effective therapeutic method in the treatment of CHD.
4.2 The word "dredging" has double indications:first,it is to dredge the obstructed heart meridian;second,it is to facilitate vessel regensis around the former obstructed vessels to help local tissue regain blood perfusion.
4.3 WRAE theory has a certain promoting effect on angiogenesis in both CAM and AMI rats models.
4.4 The mechanisms of WRAE theory in promoting angiogenesis may be related to its upregulating the expression levels of the proteins and mRNA of VEGF,bFGF in the margins of infarcted mycardium.
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