益气活血中药对心梗大鼠冠脉微血管功能障碍及相关分子调控机制的研究
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摘要
冠脉微循环是指心脏微动脉和小静脉之间的血液循环,心肌微循环障碍会影响微循环灌注,引起心肌缺血。目前,对心肌微循环的血流灌注水平越来越受到重视,深入了解心肌微循环灌注情况可为治疗心肌缺血提供帮助。
各种在冠脉病变基础上导致心肌微循环发生机械性或功能性闭塞的因素都会造成心肌微循环灌注不足。即使无明显冠脉大血管狭窄,但有微循环功能障碍造成微循环灌注不足,也会导致临床不良事件的发生,这说明冠脉微循环灌注对于评价患者预后的重要性。因此,如何维持血管的持续供血、提高组织灌注水平以及尽可能减少缺血导致的坏死,这是非常有科学意义和探索的必要性的,而改善微血管结构完整性破坏和微血管功能障碍显得尤为重要。
目的从益气活血药对冠脉微血管损伤的影响及相关调控分子作用机制的角度探讨益气活血法治疗冠脉微血管功能障碍的作用机理,并试图基于中医学“心主血脉”的理论依据,分析心脏、血管和活性物质的相关功能性和组织结构基础的变化,探索“心主血脉”相关理论基础。
方法利用SD大鼠左冠状动脉结扎法制备急性心肌梗死(AMI)模型,在心电图评价的基础上将所有造模成功者随机分为模型组、益气活血组、培哚普利组及通心络组,假手术组作为对照组,一共5组。各组于术后第1天开始分别灌胃相应药物,每日1次。选择治疗后7和28天两个时间点,通过观察实验性心梗大鼠心梗病变情况及心功能相关指标变化,评估心梗模型制作的成功以及益气活血中药对心梗大鼠心肌病理组织的影响；观察心梗大鼠毛细血管周细胞和毛细血管密度的变化,以及益气活血中药对周细胞计数的影响,探讨心梗大鼠周细胞数量变化、毛细血管密度及微血管功能障碍之间的关系；通过观察益气活血中药对心梗大鼠心肌组织中内皮细胞蛋白C受体(EPCR)、血栓调节蛋白(TM)的mRNA及蛋白表达水平的影响,观察益气活血药如何从基因蛋白水平保护血管内皮的功能,改善冠脉微血管功能障碍；观测心肌梗死边缘区NF-kB的阳性表达及血清TNF-α水平了解益气活血中药通过调节心肌NF-kB表达和血清TNF-α水平来调节冠脉微血管的功能障碍；观察益气活血中药对心梗大鼠血清TM、EPCR水平变化和NO/ET-1、PGI2/TXA2水平变化,为探讨益气活血中药对血管损伤活性物质的调控机制提供依据。
结果实验研究包括五个部分
实验一,主要是成功建立大鼠心肌梗死的模型,比较造模后模型组与假手术组大鼠术前术后心电图：假手术组大鼠手术前后心电图未见明显变化；模型组大鼠术后结扎前降支即可见心电图Ⅱ导联ST段抬高并持续存在,与术前比较有动态变化；HE染色普通光镜观察,假手术组心肌细胞排列整齐,未见心肌细胞肥大现象；模型组部分心肌细胞核较假手术组明显增大,心肌纤维增粗；术后5天造模成功的大鼠ECG显示,在I,avLV1—V6导联能不同程度的形成病理性Q波,且Q波数除假手术组外各组间无差异,从而证明心梗模型是成功的,且具有一定的稳定性。较假手术组相比,模型组左室内径(LVD)增加,左室后壁厚度(LVPWT)减少,无统计学差异,益气活血组、培哚普利组、通心络组较模型组LVD略减少、LVPWT略有增加,无统计学意义。模型组较假手术组射血分数(EF)和短轴缩短率(FS)明显缩小,有非常显著性差异(P<0.01),益气活血组、培哚普利组、通心络组较模型组EF和FS增加,有显著性差异(P<0.01或P<0.05)。
实验二,用CD34因子阳性染色免疫组化法检测益气活血中药对心肌梗死模型大鼠梗塞边缘区毛细血管密度的影响,用抗β-SMA抗体阳性染色免疫组化法检测益气活血中药对心肌梗死模型大鼠梗塞边缘区周细胞的影响：结果模型组较假手术组MCD明显下降,有非常显著性差异(P<0.01),益气活血组、培哚普利组和通心络组均可看到MCD增加,较模型组毛细血管密度明显增加,有非常显著性差异(P<0.01)；模型组周细胞计数明显增加,较假手术组有非常显著性差异(P<0.01),益气活血组、培哚普利组及通心络组周细胞数明显下降,较模型组有非常显著性差异(P<0.01)。
实验三,用RT-PCR和Western blot技术检测益气活血中药对心肌梗死模型大鼠梗塞边缘区EPCR、TM的mRNA和蛋白表达的影响,结果：给药后模型组与假手术组比较,模型组大鼠心肌组织中EPCR、TM的mRNA含量明显升高,有非常显著性差异(P<0.01),益气活血组、培哚普利组及通心络组与模型组比较,EPCR、TM的mRNA含量下降,有非常显著性差异(P<0.01),其中培哚普利的作用好于益气活血组和通心络组,后两者之间无明显差异。给药后模型组与假手术组比较,模型组大鼠心肌组织中EPCR、TM的蛋白表达明显下降,有非常显著性差异(P<0.01),益气活血组、培哚普利组及通心络组EPCR、TM的蛋白表达较模型组升高,有显著性差异(P<0.01或P<0.05)。
实验四,通过Elisa法检测益气活血方药对心肌梗死模型大鼠血清sTM及sEPCR水平的影响,结果显示：模型组与假手术组比较,模型组大鼠血清EPCR、TM含量明显升高,有非常显著性差异(P<0.01),与模型组比较,益气活血组、培哚普利组及通心络组EPCR、TM含量下降,有非常显著性差异(P<0.01)。
实验五,用免疫组化方法检测心肌梗死模型大鼠梗塞边缘区心肌组织NF-kB的表达,用Elisa法检测血清TNF-α的水平,观察益气活血中药对这两个指标的影响,结果显示给药7天：模型组大鼠血清TNF-α含量和心肌NF-kB阳性率表达与假手术组比较明显升高,有非常显著性差异(P<0.01)；与模型组比较,培哚普利组TNF-α含量和NF-kB阳性率表达降低,益气活血组和通心络组血清TNF-α含量和NF-kB阳性率表达降低明显,有显著统计学差异(P<0.05或P<0.01)；给药28天：与假手术组比较,模型组血清TNF-a含量、心肌NF-kB阳性率表达明显升高,有非常显著性差异(P<0.01)；与模型组比较,益气活血组和通心络组TNF-a含量、心肌NF-kB阳性率表达有降低趋势,培哚普利组血清TNF-α含量及心肌NF-kB阳性率表达明显降低,有显著统计学差异(P<0.05或P<0.01)。
实验六,通过Elisa法检测益气活血方药对心肌梗死模型大鼠血清NO/ET-1,PGI2/TXA2水平的影响,结果显示：模型组与假手术组比较,模型组大鼠血清ET-1、TXA2含量明显升高,NO、PGI2水平下降,有非常显著性差异(P<0.01),与模型组比较,益气活血组、培哚普利组及通心络组ET-1、TXA2含量下降,NO,PGI2水平明显升高,有显著统计学差异(P<0.05或P<0.01)。
结论：益气活血方改善心梗大鼠冠脉微循环功能障碍疗效确切,益气活血药可以降低毛细血管周细胞计数,维持血管的相对完整性,改善局部微循环的血流,减少梗死面积,并增加毛细血管密度促进血管新生,从而达到改善局部心肌血供的作用；从基因蛋白水平保护血管内皮功能,调节内源性血管收缩和舒张活性物质之间的平衡,改善血管痉挛,增加心肌供血,修复受损内皮细胞功能,逆转缺血、缺氧造成的细胞形态、功能、代谢的改变,增加局部心肌组织的血流灌注量,提高心肌细胞的供血,调节微循环的血流灌注,从而有效改善心肌冠脉微血管功能障碍。此外,益气活血中药可抑制心肌NF-kB表达和降低血清TNF-α水平,防止免疫、炎症造成的微循环损伤,防止心肌细胞损伤,以增加心肌血供。通过分析心脏、血管和活性物质的相关功能性和组织结构基础的变化初步探索了“心主血脉”的科学内涵,人之“血脉”由“心”所主、与气血相关,血脉运行正常是神经体液免疫系统综合调控的结果。
创新点：本文通过络病理论从“心主血脉”角度探讨了冠心病微血管功能障碍的理论与临床,具有临床研究的创新性；运用免疫组化方法、RT-PCR及蛋白印迹法技术从气血相关探讨了益气活血法调节冠心病微血管功能障碍相关分子调控的机理,具有实验研究的新颖性。
Coronary microcirculation is the blood circulation between heart venules and small arteries, the myocardial microcirculation will affect microcirculation, causing myocardial ischemia. Now we pay more and more attention to the level of perfusion of myocardial microcirculation, and to understand myocardial perfusion can be helpful to the treatment of myocardial ischemia.
A variety of mechanical or functional obstruction factors lead to myocardial microcirculation hypoperfusion on the basis of coronary artery diseas.Even in the absence of obvious coronary stenosis, but there is Microcirculation hypoperfusion caused by, which can lead to the occurrence of adverse clinical events. It indicated that the importance of coronary microcirculation to the evaluation of the prognosis of patients. Therefore, how to maintain the blood supply of blood vessels, improve perfusion level and minimize ischemia-induced necrosis, it is very scientific and necessary to explore. And to improve the integrity of the microvascular structure damage and microvascular dysfunction is particularly important.
Objective The effect of supplementing qi and activating blood circulation herbs on coronary microvascular injury and regulation of related molecular,from this perspective we explore the mechanism of supplementing qi and activating blood circulation on CMD.based on the theory of "the heart dominating blood circulation and vessels" we tried to analyze the change of function and structure of heart, blood vessels, and active substance, to explore theoretical basis of "the heart dominating blood circulation and vessels"
Methods The rat model was established by ligaturing the left anterior descending coronary artery. On the base of ECG evaluation all successfully modeled rats were randomly divided into the model group, group treated with supplementing qi and activating blood circulation herbs (Activating blood and supplementing Qi group), group treated with Perindopril (Perindopril group).group treated with with Tong xin luo Capsules (Tongxinluo group). The sham-operation group was taken as the control. There were totally5groups. Each group was administered with corresponding drugs daily after surgery, and Select the two observing points in time7th and28th days after treatment. To observe the change of experimental lesions of myocardial infarction and related indicators of cardiac function in rats to assess the success of myocardial infarction model making and the effects of supplementing qi and activating blood circulation Chinese medicinal on myocardial histopathological. To observe the changes of mRNA expression and protein of TM, EPCR of myocardial tissue intervented by supplementing qi and activating blood circulation Chinese medicinal, we learn how Yiqihuoxue drugs protect vascular endothelial function from the gene and protein levels, and how to improve coronary dysfunction. To observe the change of NF-kB expression of myocardial in infarct border zone and serum TNF-alpha level, we learn that to regulate the NF-kB expression and serum TNF-alpha level by the supplementing qi and activating blood circulation herbs we can improve coronary microvascular dysfunction. To observe the change of MCD and pericytes intervented by supplementing qi and activating blood circulation herbs, we explore the relation between them and their relation with CMD. To observe the change of serum TM、EPCR、NO、ET-1、PGI2and TXA2, it can provide the basis for ecploring the regulatory mechanism of supplementing qi and activating blood circulation herbs on active substances of vascular injury.
Results The experimental study consists of five parts
In experimental study1,mainly established rats myocardial infarction model successfully. Compared with preoperative ECG,ECG of rats in sham group had no change,while ECG of rats in myocardial infarction model had significant changes:ECG lead Ⅱ and persistent ST-segment elevation. After HE staining methods, under ordinary light microscope, myocardial cells of rats in sham group lined normally, and had no largement, while myocardial cells of rats in MI model was significant larger, and their myocardial fiber thickened significantly.ECG of rats MI model after surgery5days showed that Ⅰ, aVL, V1-V6Can guide different levels of pathological Q waves, and there were no difference in the number of Q-wave in different groups after surgery. All these signs verified the success of establishing the MI model and having a certain degree of stability. Compared with the sham-operation group, the LVD increased and the LVPWT decreased in the model group,while the LVD decreased and the LVPWT increased a little in the Activating-blood and supplementing-Qi group, Perindopril group and Tongxinluo group compared with the model group,all these has no statistically significant. Compared with the sham-operation group,the EF and FS decreased significantly in the model group(P<0.01),while the EF and FS increased significantly in the Activating-blood and supplementing-Qi group, Perindopril group and Tongxinluo group compared with the model group(P<0.05or P<0.01).
In experimental study2, to observe the changes of mRNA expression and protein of TM, EPCR of myocardial tissue in myocardial infarct border zone measured by real-time PCR and western blot separately. After administration,compared with the sham-operation group, the expression of EPCR and TM of myocardial tissue in the model group increased significantly(P<0.01);the serum levels of TM and EPCR decreased significantly in the Activating-blood and supplementing-Qi group, Perindopril group and Tongxinluo group compared with the model group(P<0.01),especially Perindopril group.After administration,compared with the sham-operation group, the protein of EPCR and TM of myocardial tissue in the model group decreased significantly(P<0.01); the protein of TM and EPCR increased significantly in the activating-blood and supplementing-qi group, perindopril group and tongxinluo group compared with the model group(P<0.01or<0.05).
In experimental study3, to observe the change of MCD and pericytes in myocardial infarct border zone measured by CD34factor positive staining immunohisto-chemistry method and anti-alpha-SMA antibody positive immunohistochemical method separately after intervented with supplementing qi and activating blood circulation herbs. It showed, the MVD decreased significantly in the model group and the number of capillary pericytes increased compared with the sham-opevation group(P<0.01).The MVD increased significantly in the activating-blood and supplementing-qi group, perindopril group and tongxinluo group compared with the model group(P<0.01).
In experimental study4, to observe the effects of supplementing qi and activating blood circulation herbs on serum TM and EPCR, it showed that the serum levels of TM and EPCR decreased significantly in the model group compared with the sham-operation group(P<0.01) and the serum levels of TM and EPCR decreased significantly in the activating-blood and supplementing-qi group, perindopril group and tongxinluo group compared with the model group(P<0.01).
In experimental study5, to detect the positive expression of NF-kB in myo-cardial infarct border zone measured by immunohistochemical method,and to detect the serum level of TNF-α measured by Elisa. The results showed that on the7th day the serum level of TNF-a and the positive expression of NF-kB increased significantly in the model group compared with the sham-operation group(P<0.01); the serum level of TNF-α and the positive expression of NF-kB decreased significantly in the activating-blood and supplementing-qi group, perindopril group and tongxinluo group compared with the model group(P<0.05or P<0.01). On the28th day the serum level of TNF-α and the positive expression of NF-kB increased significantly in the model group compared with the sham-operation group(P<0.01); the serum level of TNF-α and the positive expression of NF-kB decreased significantly in the activating-blood and supplementing-qi group,perindopril group and tongxinluo group compared with the model group(P<0.05or P<0.01),especially the Perindopril group.
In experimental study6, to observe the effects of supplementing qi and activating blood circulation herbs on serum NO,ET-1,PGI2and TXA2, it showed that the serum levels of ET-1and TXA2increased,while the serum levels of NO and PGI2decreased significantly in the model group compared with the sham-operation group (P<0.01).The serum levels of ET-1and TXA2decreased,while the serum levels of NO and PGI2increased significantly in the Activating-blood and supplementing-Qi group,Perindopril group and Tongxinluo group compared with the model group(P<0.05or P<0.01).
Conclusion To administrate the supplementing qi and activating blood circulation herbs can improve coronary microvascular dysfunction in myocardial infarction rat effectively, and reduce the count of capillary pericytes, maintain the relative integrity of blood vessels, improve the blood flow of local microcirculation, reduce infarct size and increase the MCD to promote angiogenesis, so as to improve the role of regional myocardial blood supply. It can protect the function of vascular endothelial at gene protein levels, and adjust the balance between the endogenous vasoconstrictor substance and vasodilator substance, improve vascular spasm, increase myocardial blood supply, and repair the function of impaired endothelial cell, reverse the changes of cell morphology,function, metabolize caused by ischemia and hypoxia, increase regional myocardial tissue perfusion and blood supply to myocardial cells,and regulate microcirculation perfusion, in order to improve myocardial coronary microvascular dysfunction effectively.In addition, supplementing qi and activating blood circulation herbs can inhibit the expression of NF-kB and reduce serum level of TNF-alpha, to prevent the microcirculation damage caused by immunity and inflammation, prevent damage myocardial cells, in order to increase myocardial blood supply.To analyze the change of function and structure of heart, blood vessels, and active substance we explored the scientific connotation of "the heart dominating blood circulation and vessels" preliminarily,"blood vessels" are dominated by the "heart",and related with blood. The "blood" running normally is the results of regulation by neurohormonal immune system.
Innovation In this paper, through the theory of collateral disease we explored the theory and clinical of CMD research from the perspective of "the heart dominating blood circulation and vessels"', it's an innovative clinical research. Using immunohistochemical methods, RT-PCR and Western blot technique we explore the regulatory mechanism of CMD with supplementing qi and activating blood circulation herbs from the relation with "the heart dominating blood circulation and vessels", it's an experimental study with the novelty.
各种在冠脉病变基础上导致心肌微循环发生机械性或功能性闭塞的因素都会造成心肌微循环灌注不足。即使无明显冠脉大血管狭窄,但有微循环功能障碍造成微循环灌注不足,也会导致临床不良事件的发生,这说明冠脉微循环灌注对于评价患者预后的重要性。因此,如何维持血管的持续供血、提高组织灌注水平以及尽可能减少缺血导致的坏死,这是非常有科学意义和探索的必要性的,而改善微血管结构完整性破坏和微血管功能障碍显得尤为重要。
目的从益气活血药对冠脉微血管损伤的影响及相关调控分子作用机制的角度探讨益气活血法治疗冠脉微血管功能障碍的作用机理,并试图基于中医学“心主血脉”的理论依据,分析心脏、血管和活性物质的相关功能性和组织结构基础的变化,探索“心主血脉”相关理论基础。
方法利用SD大鼠左冠状动脉结扎法制备急性心肌梗死(AMI)模型,在心电图评价的基础上将所有造模成功者随机分为模型组、益气活血组、培哚普利组及通心络组,假手术组作为对照组,一共5组。各组于术后第1天开始分别灌胃相应药物,每日1次。选择治疗后7和28天两个时间点,通过观察实验性心梗大鼠心梗病变情况及心功能相关指标变化,评估心梗模型制作的成功以及益气活血中药对心梗大鼠心肌病理组织的影响；观察心梗大鼠毛细血管周细胞和毛细血管密度的变化,以及益气活血中药对周细胞计数的影响,探讨心梗大鼠周细胞数量变化、毛细血管密度及微血管功能障碍之间的关系；通过观察益气活血中药对心梗大鼠心肌组织中内皮细胞蛋白C受体(EPCR)、血栓调节蛋白(TM)的mRNA及蛋白表达水平的影响,观察益气活血药如何从基因蛋白水平保护血管内皮的功能,改善冠脉微血管功能障碍；观测心肌梗死边缘区NF-kB的阳性表达及血清TNF-α水平了解益气活血中药通过调节心肌NF-kB表达和血清TNF-α水平来调节冠脉微血管的功能障碍；观察益气活血中药对心梗大鼠血清TM、EPCR水平变化和NO/ET-1、PGI2/TXA2水平变化,为探讨益气活血中药对血管损伤活性物质的调控机制提供依据。
结果实验研究包括五个部分
实验一,主要是成功建立大鼠心肌梗死的模型,比较造模后模型组与假手术组大鼠术前术后心电图：假手术组大鼠手术前后心电图未见明显变化；模型组大鼠术后结扎前降支即可见心电图Ⅱ导联ST段抬高并持续存在,与术前比较有动态变化；HE染色普通光镜观察,假手术组心肌细胞排列整齐,未见心肌细胞肥大现象；模型组部分心肌细胞核较假手术组明显增大,心肌纤维增粗；术后5天造模成功的大鼠ECG显示,在I,avLV1—V6导联能不同程度的形成病理性Q波,且Q波数除假手术组外各组间无差异,从而证明心梗模型是成功的,且具有一定的稳定性。较假手术组相比,模型组左室内径(LVD)增加,左室后壁厚度(LVPWT)减少,无统计学差异,益气活血组、培哚普利组、通心络组较模型组LVD略减少、LVPWT略有增加,无统计学意义。模型组较假手术组射血分数(EF)和短轴缩短率(FS)明显缩小,有非常显著性差异(P<0.01),益气活血组、培哚普利组、通心络组较模型组EF和FS增加,有显著性差异(P<0.01或P<0.05)。
实验二,用CD34因子阳性染色免疫组化法检测益气活血中药对心肌梗死模型大鼠梗塞边缘区毛细血管密度的影响,用抗β-SMA抗体阳性染色免疫组化法检测益气活血中药对心肌梗死模型大鼠梗塞边缘区周细胞的影响：结果模型组较假手术组MCD明显下降,有非常显著性差异(P<0.01),益气活血组、培哚普利组和通心络组均可看到MCD增加,较模型组毛细血管密度明显增加,有非常显著性差异(P<0.01)；模型组周细胞计数明显增加,较假手术组有非常显著性差异(P<0.01),益气活血组、培哚普利组及通心络组周细胞数明显下降,较模型组有非常显著性差异(P<0.01)。
实验三,用RT-PCR和Western blot技术检测益气活血中药对心肌梗死模型大鼠梗塞边缘区EPCR、TM的mRNA和蛋白表达的影响,结果：给药后模型组与假手术组比较,模型组大鼠心肌组织中EPCR、TM的mRNA含量明显升高,有非常显著性差异(P<0.01),益气活血组、培哚普利组及通心络组与模型组比较,EPCR、TM的mRNA含量下降,有非常显著性差异(P<0.01),其中培哚普利的作用好于益气活血组和通心络组,后两者之间无明显差异。给药后模型组与假手术组比较,模型组大鼠心肌组织中EPCR、TM的蛋白表达明显下降,有非常显著性差异(P<0.01),益气活血组、培哚普利组及通心络组EPCR、TM的蛋白表达较模型组升高,有显著性差异(P<0.01或P<0.05)。
实验四,通过Elisa法检测益气活血方药对心肌梗死模型大鼠血清sTM及sEPCR水平的影响,结果显示：模型组与假手术组比较,模型组大鼠血清EPCR、TM含量明显升高,有非常显著性差异(P<0.01),与模型组比较,益气活血组、培哚普利组及通心络组EPCR、TM含量下降,有非常显著性差异(P<0.01)。
实验五,用免疫组化方法检测心肌梗死模型大鼠梗塞边缘区心肌组织NF-kB的表达,用Elisa法检测血清TNF-α的水平,观察益气活血中药对这两个指标的影响,结果显示给药7天：模型组大鼠血清TNF-α含量和心肌NF-kB阳性率表达与假手术组比较明显升高,有非常显著性差异(P<0.01)；与模型组比较,培哚普利组TNF-α含量和NF-kB阳性率表达降低,益气活血组和通心络组血清TNF-α含量和NF-kB阳性率表达降低明显,有显著统计学差异(P<0.05或P<0.01)；给药28天：与假手术组比较,模型组血清TNF-a含量、心肌NF-kB阳性率表达明显升高,有非常显著性差异(P<0.01)；与模型组比较,益气活血组和通心络组TNF-a含量、心肌NF-kB阳性率表达有降低趋势,培哚普利组血清TNF-α含量及心肌NF-kB阳性率表达明显降低,有显著统计学差异(P<0.05或P<0.01)。
实验六,通过Elisa法检测益气活血方药对心肌梗死模型大鼠血清NO/ET-1,PGI2/TXA2水平的影响,结果显示：模型组与假手术组比较,模型组大鼠血清ET-1、TXA2含量明显升高,NO、PGI2水平下降,有非常显著性差异(P<0.01),与模型组比较,益气活血组、培哚普利组及通心络组ET-1、TXA2含量下降,NO,PGI2水平明显升高,有显著统计学差异(P<0.05或P<0.01)。
结论：益气活血方改善心梗大鼠冠脉微循环功能障碍疗效确切,益气活血药可以降低毛细血管周细胞计数,维持血管的相对完整性,改善局部微循环的血流,减少梗死面积,并增加毛细血管密度促进血管新生,从而达到改善局部心肌血供的作用；从基因蛋白水平保护血管内皮功能,调节内源性血管收缩和舒张活性物质之间的平衡,改善血管痉挛,增加心肌供血,修复受损内皮细胞功能,逆转缺血、缺氧造成的细胞形态、功能、代谢的改变,增加局部心肌组织的血流灌注量,提高心肌细胞的供血,调节微循环的血流灌注,从而有效改善心肌冠脉微血管功能障碍。此外,益气活血中药可抑制心肌NF-kB表达和降低血清TNF-α水平,防止免疫、炎症造成的微循环损伤,防止心肌细胞损伤,以增加心肌血供。通过分析心脏、血管和活性物质的相关功能性和组织结构基础的变化初步探索了“心主血脉”的科学内涵,人之“血脉”由“心”所主、与气血相关,血脉运行正常是神经体液免疫系统综合调控的结果。
创新点：本文通过络病理论从“心主血脉”角度探讨了冠心病微血管功能障碍的理论与临床,具有临床研究的创新性；运用免疫组化方法、RT-PCR及蛋白印迹法技术从气血相关探讨了益气活血法调节冠心病微血管功能障碍相关分子调控的机理,具有实验研究的新颖性。
Coronary microcirculation is the blood circulation between heart venules and small arteries, the myocardial microcirculation will affect microcirculation, causing myocardial ischemia. Now we pay more and more attention to the level of perfusion of myocardial microcirculation, and to understand myocardial perfusion can be helpful to the treatment of myocardial ischemia.
A variety of mechanical or functional obstruction factors lead to myocardial microcirculation hypoperfusion on the basis of coronary artery diseas.Even in the absence of obvious coronary stenosis, but there is Microcirculation hypoperfusion caused by, which can lead to the occurrence of adverse clinical events. It indicated that the importance of coronary microcirculation to the evaluation of the prognosis of patients. Therefore, how to maintain the blood supply of blood vessels, improve perfusion level and minimize ischemia-induced necrosis, it is very scientific and necessary to explore. And to improve the integrity of the microvascular structure damage and microvascular dysfunction is particularly important.
Objective The effect of supplementing qi and activating blood circulation herbs on coronary microvascular injury and regulation of related molecular,from this perspective we explore the mechanism of supplementing qi and activating blood circulation on CMD.based on the theory of "the heart dominating blood circulation and vessels" we tried to analyze the change of function and structure of heart, blood vessels, and active substance, to explore theoretical basis of "the heart dominating blood circulation and vessels"
Methods The rat model was established by ligaturing the left anterior descending coronary artery. On the base of ECG evaluation all successfully modeled rats were randomly divided into the model group, group treated with supplementing qi and activating blood circulation herbs (Activating blood and supplementing Qi group), group treated with Perindopril (Perindopril group).group treated with with Tong xin luo Capsules (Tongxinluo group). The sham-operation group was taken as the control. There were totally5groups. Each group was administered with corresponding drugs daily after surgery, and Select the two observing points in time7th and28th days after treatment. To observe the change of experimental lesions of myocardial infarction and related indicators of cardiac function in rats to assess the success of myocardial infarction model making and the effects of supplementing qi and activating blood circulation Chinese medicinal on myocardial histopathological. To observe the changes of mRNA expression and protein of TM, EPCR of myocardial tissue intervented by supplementing qi and activating blood circulation Chinese medicinal, we learn how Yiqihuoxue drugs protect vascular endothelial function from the gene and protein levels, and how to improve coronary dysfunction. To observe the change of NF-kB expression of myocardial in infarct border zone and serum TNF-alpha level, we learn that to regulate the NF-kB expression and serum TNF-alpha level by the supplementing qi and activating blood circulation herbs we can improve coronary microvascular dysfunction. To observe the change of MCD and pericytes intervented by supplementing qi and activating blood circulation herbs, we explore the relation between them and their relation with CMD. To observe the change of serum TM、EPCR、NO、ET-1、PGI2and TXA2, it can provide the basis for ecploring the regulatory mechanism of supplementing qi and activating blood circulation herbs on active substances of vascular injury.
Results The experimental study consists of five parts
In experimental study1,mainly established rats myocardial infarction model successfully. Compared with preoperative ECG,ECG of rats in sham group had no change,while ECG of rats in myocardial infarction model had significant changes:ECG lead Ⅱ and persistent ST-segment elevation. After HE staining methods, under ordinary light microscope, myocardial cells of rats in sham group lined normally, and had no largement, while myocardial cells of rats in MI model was significant larger, and their myocardial fiber thickened significantly.ECG of rats MI model after surgery5days showed that Ⅰ, aVL, V1-V6Can guide different levels of pathological Q waves, and there were no difference in the number of Q-wave in different groups after surgery. All these signs verified the success of establishing the MI model and having a certain degree of stability. Compared with the sham-operation group, the LVD increased and the LVPWT decreased in the model group,while the LVD decreased and the LVPWT increased a little in the Activating-blood and supplementing-Qi group, Perindopril group and Tongxinluo group compared with the model group,all these has no statistically significant. Compared with the sham-operation group,the EF and FS decreased significantly in the model group(P<0.01),while the EF and FS increased significantly in the Activating-blood and supplementing-Qi group, Perindopril group and Tongxinluo group compared with the model group(P<0.05or P<0.01).
In experimental study2, to observe the changes of mRNA expression and protein of TM, EPCR of myocardial tissue in myocardial infarct border zone measured by real-time PCR and western blot separately. After administration,compared with the sham-operation group, the expression of EPCR and TM of myocardial tissue in the model group increased significantly(P<0.01);the serum levels of TM and EPCR decreased significantly in the Activating-blood and supplementing-Qi group, Perindopril group and Tongxinluo group compared with the model group(P<0.01),especially Perindopril group.After administration,compared with the sham-operation group, the protein of EPCR and TM of myocardial tissue in the model group decreased significantly(P<0.01); the protein of TM and EPCR increased significantly in the activating-blood and supplementing-qi group, perindopril group and tongxinluo group compared with the model group(P<0.01or<0.05).
In experimental study3, to observe the change of MCD and pericytes in myocardial infarct border zone measured by CD34factor positive staining immunohisto-chemistry method and anti-alpha-SMA antibody positive immunohistochemical method separately after intervented with supplementing qi and activating blood circulation herbs. It showed, the MVD decreased significantly in the model group and the number of capillary pericytes increased compared with the sham-opevation group(P<0.01).The MVD increased significantly in the activating-blood and supplementing-qi group, perindopril group and tongxinluo group compared with the model group(P<0.01).
In experimental study4, to observe the effects of supplementing qi and activating blood circulation herbs on serum TM and EPCR, it showed that the serum levels of TM and EPCR decreased significantly in the model group compared with the sham-operation group(P<0.01) and the serum levels of TM and EPCR decreased significantly in the activating-blood and supplementing-qi group, perindopril group and tongxinluo group compared with the model group(P<0.01).
In experimental study5, to detect the positive expression of NF-kB in myo-cardial infarct border zone measured by immunohistochemical method,and to detect the serum level of TNF-α measured by Elisa. The results showed that on the7th day the serum level of TNF-a and the positive expression of NF-kB increased significantly in the model group compared with the sham-operation group(P<0.01); the serum level of TNF-α and the positive expression of NF-kB decreased significantly in the activating-blood and supplementing-qi group, perindopril group and tongxinluo group compared with the model group(P<0.05or P<0.01). On the28th day the serum level of TNF-α and the positive expression of NF-kB increased significantly in the model group compared with the sham-operation group(P<0.01); the serum level of TNF-α and the positive expression of NF-kB decreased significantly in the activating-blood and supplementing-qi group,perindopril group and tongxinluo group compared with the model group(P<0.05or P<0.01),especially the Perindopril group.
In experimental study6, to observe the effects of supplementing qi and activating blood circulation herbs on serum NO,ET-1,PGI2and TXA2, it showed that the serum levels of ET-1and TXA2increased,while the serum levels of NO and PGI2decreased significantly in the model group compared with the sham-operation group (P<0.01).The serum levels of ET-1and TXA2decreased,while the serum levels of NO and PGI2increased significantly in the Activating-blood and supplementing-Qi group,Perindopril group and Tongxinluo group compared with the model group(P<0.05or P<0.01).
Conclusion To administrate the supplementing qi and activating blood circulation herbs can improve coronary microvascular dysfunction in myocardial infarction rat effectively, and reduce the count of capillary pericytes, maintain the relative integrity of blood vessels, improve the blood flow of local microcirculation, reduce infarct size and increase the MCD to promote angiogenesis, so as to improve the role of regional myocardial blood supply. It can protect the function of vascular endothelial at gene protein levels, and adjust the balance between the endogenous vasoconstrictor substance and vasodilator substance, improve vascular spasm, increase myocardial blood supply, and repair the function of impaired endothelial cell, reverse the changes of cell morphology,function, metabolize caused by ischemia and hypoxia, increase regional myocardial tissue perfusion and blood supply to myocardial cells,and regulate microcirculation perfusion, in order to improve myocardial coronary microvascular dysfunction effectively.In addition, supplementing qi and activating blood circulation herbs can inhibit the expression of NF-kB and reduce serum level of TNF-alpha, to prevent the microcirculation damage caused by immunity and inflammation, prevent damage myocardial cells, in order to increase myocardial blood supply.To analyze the change of function and structure of heart, blood vessels, and active substance we explored the scientific connotation of "the heart dominating blood circulation and vessels" preliminarily,"blood vessels" are dominated by the "heart",and related with blood. The "blood" running normally is the results of regulation by neurohormonal immune system.
Innovation In this paper, through the theory of collateral disease we explored the theory and clinical of CMD research from the perspective of "the heart dominating blood circulation and vessels"', it's an innovative clinical research. Using immunohistochemical methods, RT-PCR and Western blot technique we explore the regulatory mechanism of CMD with supplementing qi and activating blood circulation herbs from the relation with "the heart dominating blood circulation and vessels", it's an experimental study with the novelty.
引文
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