七龙天对低氧性肺动脉高压大鼠VEGF及Ang-1的影响
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摘要
目的:观察七龙天对低氧性肺动脉高压(HPH)大鼠血管内皮生长因子(VEGF)、血管形成因子-1(Ang-1)的影响。方法:将雄性SD大鼠随机分为6组:正常组,模型组,波生坦组,七龙天低、中、高剂量组。正常组大鼠置于正常环境中饲养,除正常组外所有实验大鼠均采用常压低氧法制模,从制模第1天开始给药,连续3周。在直视下行右心导管术测定肺血流动力学参数,以RT-PCR法检测肺组织中VEGF、Ang-1 mRNA表达及免疫组织化学技术检测VEGF、Ang-1在肺小动脉内膜中的蛋白表达。结果:HPH大鼠肺小动脉管壁增厚,管腔狭窄甚至闭塞,七龙天各剂量组及波生坦组均能改善管壁增厚,尤其是七龙天高剂量组肺小动脉管壁光滑,管腔通畅,接近正常组。与模型组比较,七龙天各剂量组及波生坦组均可显著降低大鼠PASP及MPAP(P<0.05,P<0.01),且以七龙天高剂量组效果为佳。七龙天各剂量组VEGF mRNA及蛋白表达下调表达水平均优于波生坦组(P<0.05,P<0.01),且以七龙天高剂量组为显著。七龙天中、高剂量组较模型组及波生坦组可显著下调其Ang-1 mRNA表达水平(P<0.05)。结论:七龙天可降低肺动脉高压,且七龙天高剂量组疗效优于波生坦组。其降压机制与降低VEGF表达量有关,与Ang-1的表达还需进一步研究。
Objective: To study the effects of Qilongtian on vascular endothelial growth factor(VEGF) and angiopoietin-1(Ang-1) in the hypoxic pulmonary hypertension(HPH) rats. Methods: All male SD rats were randomly divided into six groups: normal group, model group, Bosentan group, Qilongtian high-, mid-and low-dose group. Except the rats in normal group, those in other five groups were under atmospheric hypoxia to establish HPH model. From the first day of modeling,all medication groups were i.g. corresponding drugs for consecutive three weeks. Pulmonary hemodynamic parameters were detected by right heart catheterization under direct vision, mRNA expression of VEGF and Ang-1 in lung tissue were measured by ELISA, protein expression of VEGF and Ang-1 in lung tissue were measured by immunohistochemically methods. Results:The wall of pulmonary arterioles in HPH rats was thickened, the lumen was narrowed or even occluded. Qilongtian and Bosentan could improve the wall thickening. The wall of pulmonary arterioles in Qilongtian high-dose group was smooth and unobstructed,close to the normal group. Compared with the model group, each dose of Qilongtian and Bosentan group could significantly reduce PASP and MPAP in rats(P<0.05, P<0.01), and the effect of Qilongtian high-dose group was better. The down-regulated expression level of VEGF in Qilongtian group was better than that in Bosentan group(P<0.05, P<0.01), and the high-dose group was significant(P<0.05, P<0.01). Compared with model group and Bosentan group, Qilongtian med-and high-dose group could down-regulate the expression of Ang-1 mRNA(P<0.05). Conclusion: The different dose of Qilongtian can reduce pulmonary hypertension, and high dose Qilongtian curative effect is better than that of Bosentan. Its antihypertensive mechanism is related to the reduction of VEGF expression, and the expression of Ang-1 needs to be further studied.
Objective: To study the effects of Qilongtian on vascular endothelial growth factor(VEGF) and angiopoietin-1(Ang-1) in the hypoxic pulmonary hypertension(HPH) rats. Methods: All male SD rats were randomly divided into six groups: normal group, model group, Bosentan group, Qilongtian high-, mid-and low-dose group. Except the rats in normal group, those in other five groups were under atmospheric hypoxia to establish HPH model. From the first day of modeling,all medication groups were i.g. corresponding drugs for consecutive three weeks. Pulmonary hemodynamic parameters were detected by right heart catheterization under direct vision, mRNA expression of VEGF and Ang-1 in lung tissue were measured by ELISA, protein expression of VEGF and Ang-1 in lung tissue were measured by immunohistochemically methods. Results:The wall of pulmonary arterioles in HPH rats was thickened, the lumen was narrowed or even occluded. Qilongtian and Bosentan could improve the wall thickening. The wall of pulmonary arterioles in Qilongtian high-dose group was smooth and unobstructed,close to the normal group. Compared with the model group, each dose of Qilongtian and Bosentan group could significantly reduce PASP and MPAP in rats(P<0.05, P<0.01), and the effect of Qilongtian high-dose group was better. The down-regulated expression level of VEGF in Qilongtian group was better than that in Bosentan group(P<0.05, P<0.01), and the high-dose group was significant(P<0.05, P<0.01). Compared with model group and Bosentan group, Qilongtian med-and high-dose group could down-regulate the expression of Ang-1 mRNA(P<0.05). Conclusion: The different dose of Qilongtian can reduce pulmonary hypertension, and high dose Qilongtian curative effect is better than that of Bosentan. Its antihypertensive mechanism is related to the reduction of VEGF expression, and the expression of Ang-1 needs to be further studied.
引文
[1]盖祥云,林鹏程,何彦峰,等.低氧性肺动脉高压中低氧性肺血管收缩的作用.中国药理学通报,2016,32(6):768-772
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[6]郭凌宇,魏瑞鹏,贾永平.血管生成素1,2/Tie2系统在心血管疾病中的研究进展.中西医结合心脑血管病杂志,2018,16(3):302-305
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[10]Yang X,Zhu H,Ge Y,et al.Melittin enhances radiosensitivity of hypoxic head and neck squamous cell carcinoma by suppressing HIF-1α.Tumour Biol,2014,35(10):10443-10448
[11]阿得力·艾山.三七总皂苷对心肌梗死大鼠血管新生及VEGF表达的影响.中西医结合心脑血管病杂志,2016,14(15):1732-1735
[12]王雁彬,李廷荃,化金凤,等.三七对大鼠下肢缺血模型MVD及VEGF蛋白表达的影响.中西医结合心脑血管病杂志,2016,14(4):371-372
[13]李善华,黄萍,陈琴,等.红景天苷对博莱霉素诱导大鼠肺纤维化后VEGF及MMP表达的影响.实用药物与临床,2016,19(11):1340-1343
[14]Takakura N,Watanabe T,Suenobu S,et al.A role for hematopoietic stem cells in promoting angiogenesis.Cell,2000,102(1):199-209
[15]马林枭.三七多糖对人成纤维细胞增殖活性及相关细胞因子表达能力的影响.昆明:昆明医科大学,2015
[16]Grzenda A,Shannon J,Fisher J,et al.Timing and expression of the angiopoietin-1-Tie-2 pathway in murine lung development and congenital diaphragmatic hernia.Dis Model Mech,2013,6(1):106-114
[17]王伟,王治平,方丹青.血管生成素-1和血管生成素-2在先天性心脏病肺动脉高压形成中的变化和意义.中国现代医学杂志,2015,25(10):28-35
[2]LAHM T,ALBRECHT M,FISHER A J,et al.17β-Estradiol attenuates hypoxic pulmonary hypertension via estrogen receptormediated effects.Am J Respir Crit Care Med,2012,185(9):965-980
[3]Klinger J R,Abman S H,Gladwin M T.Nitric oxide deficiency and endothelial dysfunction in pulmonary arterial hypertension.Am JRespir Crit Care Med,2013,188(6):639-646
[4]Institute for Health Metrics and Evaluation(IHME).The Global Burden of Disease:Generating Evidence,Guiding Policy.Seattle,2013-8-27
[5]冯恩志,黄宁侠,杨生岳,等.高原低氧性肺动脉高压与肺血管内皮功能的相关性研究.中华肺部疾病杂志(电子版),2016,9(3):248-251
[6]郭凌宇,魏瑞鹏,贾永平.血管生成素1,2/Tie2系统在心血管疾病中的研究进展.中西医结合心脑血管病杂志,2018,16(3):302-305
[7]高阳,刘杰,王蕾,等.两种低氧性肺动脉高压小鼠模型的建立与比较.首都医科大学学报,2018,39(4):563-568
[8]徐叔云,卞如濂,陈修.药理实验方法学.北京:人民卫生出版社,2002
[9]赵帅,张博.低氧性肺动脉高压的研究进展.广东医学,2018,39(S2):268-270
[10]Yang X,Zhu H,Ge Y,et al.Melittin enhances radiosensitivity of hypoxic head and neck squamous cell carcinoma by suppressing HIF-1α.Tumour Biol,2014,35(10):10443-10448
[11]阿得力·艾山.三七总皂苷对心肌梗死大鼠血管新生及VEGF表达的影响.中西医结合心脑血管病杂志,2016,14(15):1732-1735
[12]王雁彬,李廷荃,化金凤,等.三七对大鼠下肢缺血模型MVD及VEGF蛋白表达的影响.中西医结合心脑血管病杂志,2016,14(4):371-372
[13]李善华,黄萍,陈琴,等.红景天苷对博莱霉素诱导大鼠肺纤维化后VEGF及MMP表达的影响.实用药物与临床,2016,19(11):1340-1343
[14]Takakura N,Watanabe T,Suenobu S,et al.A role for hematopoietic stem cells in promoting angiogenesis.Cell,2000,102(1):199-209
[15]马林枭.三七多糖对人成纤维细胞增殖活性及相关细胞因子表达能力的影响.昆明:昆明医科大学,2015
[16]Grzenda A,Shannon J,Fisher J,et al.Timing and expression of the angiopoietin-1-Tie-2 pathway in murine lung development and congenital diaphragmatic hernia.Dis Model Mech,2013,6(1):106-114
[17]王伟,王治平,方丹青.血管生成素-1和血管生成素-2在先天性心脏病肺动脉高压形成中的变化和意义.中国现代医学杂志,2015,25(10):28-35