兰州大学机构库 >第一临床医学院
当归多糖通过Oip5-as1调节SIRT1-AMPK-PGC1α通路改善心肌缺血再灌注损伤的实验研究
Alternative TitleAngelica Sinensis Polysaccharide Protects against Myocardial Ischemia/Reperfusion Injury via Oip5-as1 Mediated SIRT1-AMPK-PGC1α Pathway
牛小伟
Thesis Advisor张钲
2019-09-01
Degree Grantor兰州大学
Place of Conferral兰州
Degree Name博士
Degree Discipline内科学
Keyword当归多糖 缺血再灌注损伤 长链非编码RNA
Abstract背景:急性心肌梗死(AMI)是在世界范围内发病率和死亡率较高的疾病之一。再灌注治疗是改善AMI患者预后的关键。但再灌注本身会增加心肌和冠脉循环的不可逆性损伤,导致梗死面积增加,即心肌缺血再灌注(MI/R)损伤。因此,在恢复心肌有效再灌注的基础上,采取能够改善MI/R损伤的心肌保护措施具有重要临床意义。许多中药在AMI中具有抗心肌缺血损伤、防止心室重构和保护心功能的作用,其中作为甘肃省道地药材的当归是常用药物之一。然而,当归对心肌保护作用的活性成分尚不明确,其发挥疗效的分子机制有待于进一步研究。  目的:研究当归活性成分改善MI/R损伤的作用及分子机制。  方法:1. 运用网络药理学方法筛选当归对心肌保护作用的主要活性成分及可能的信号通路(第一部分)。2. 采用体内外实验及分子生物学方法研究由网络药理学筛选出的当归活性成分—当归多糖(ASP)改善MI/R损伤的作用和SIRT1-AMPK-PGC1α信号机制(第二部分)。3. 通过实验研究ASP对lncRNA Oip5-as1的影响及Oip5-as1对SIRT1-AMPK-PGC1α信号通路的调节作用(第三部分)。             结果:1. 网络药理学发现ASP可能是当归保护心肌的重要活性成分,SIRT1-AMPK-PGC1α信号通路是潜在作用机理。2. 细胞实验发现ASP通过激活SIRT1-AMPK-PGC1α信号通路发挥保护线粒体、抗氧化应激以及减少心肌细胞凋亡的作用。3. 细胞实验显示ASP促进Oip5-as1的表达丰度。Oip5-as1作为竞争性内源RNA(ceRNA)调控SIRT1 mRNA的表达,进而激活SIRT1-AMPK-PGC1α信号通路。4. 动物实验发现ASP改善MI/R损伤,促进Oip5-as1的表达水平,上调SIRT1-AMPK-PGC1α信号通路。    结论:1. 利用网络药理学筛选当归活性成分及其在心肌保护中的作用机制是一种可行的方法。2. ASP通过上调Oip5-as1表达,激活SIRT1-AMPK-PGC1α信号通路,从而缓解氧化应激,抑制线粒体凋亡途径,最终减少细胞凋亡,改善MI/R损伤。
Other AbstractBackground: Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality worldwide. Timely restoration of myocardial blood flow is a cornerstone of the treatment of AMI. However, reperfusion itself can cause myocardial damage, namely myocardial ischemia/reperfusion (MI/R) injury. Therefore, it is clinically important to find an approach to protect against MI/R injury following timely and complete reperfusion. Both experimental and clinical studies have highlighted that herbal medicines can reduce ischemic injury and improve cardiac function after AMI. Angelica sinensis, a geoherb in Gansu, has been used in treating cardiovascular diseases. However, it remains not completely understood that the biological activities and the molecular mechanisms of action underlying cardioprotective effects of Angelica sinensis.  Objective: To study the protective effect and molecular mechanism of active components of Angelica sinensis on MI/R injury.   Methods: 1. To screen major component of Angelica Sinensis on cardioprotective role and its potential pathway using network pharmacology analysis (Part 1). 2. By means of in vitro, in vivo, and molecular biology experiments, we examined the effect of Angelica sinensis polysaccharide (ASP), the active constituent of Angelica sinensis by network pharmacology on protecting against MI/R injury. The role of ASP on SIRT1-AMPK-PGC1α signaling pathway was also analyzed (Part 2). 3. By means of experiments, we studied the action of ASP on OPA-interacting protein 5 antisense transcript 1 (Oip5-as1) expression and the detailed molecular mechanism by which Oip5-as1 regulates SIRT1-AMPK-PGC1α pathway (Part 3).Results: 1. By using network pharmacology, we found that ASP may be an important active ingredient for Angelica sinensis exerting cardioprotective effects, and SIRT1-AMPK-PGC1α pathway may be its potential mechanism. 2. ASP ameliorates the mitochondrial dysfunction, oxidative injury, and apoptosis through activating SIRT1-AMPK-PGC1α pathway in the in vitro experiments. 3. The in vitro experiments showed that ASP promotes Oip5-as1 expression. Oip5-as1 acts as a ceRNA to regulate SIRT1 mRNA expression, thereby activating the SIRT1-AMPK-PGC1α signaling pathway. 4. The in vivo experiments found that ASP treatment ameliorates MI/R injury. ASP therapy promotes the expression level of Oip5-as1 and upregulates SIRT1-AMPK-PGC1α signaling pathway.   Conclusions: 1. The network pharmacology is a feasible method to screen active ingredients of Angelica sinensis and its mechanism of action on cardioprotective role. 2. ASP upregulates the level of Oip5-as1 to activate the SIRT1-AMPK-PGC1α signaling pathway. ASP reduces oxidative stress, inhibits the mitochondrial apoptosis pathway, and ultimately reduces cell apoptosis and exerts protective effect against MI/R injury.
Pages131
URL查看原文
Language中文
Document Type学位论文
Identifierhttp://ir.lzu.edu.cn/handle/262010/338738
Collection第一临床医学院
Affiliation第一临床医学院
First Author AffilicationFirst Clinical School
Recommended Citation
GB/T 7714
牛小伟. 当归多糖通过Oip5-as1调节SIRT1-AMPK-PGC1α通路改善心肌缺血再灌注损伤的实验研究[D]. 兰州. 兰州大学,2019.
Files in This Item:
There are no files associated with this item.
Related Services
Recommend this item
Bookmark
Usage statistics
Export to Endnote
Altmetrics Score
Google Scholar
Similar articles in Google Scholar
[牛小伟]'s Articles
Baidu academic
Similar articles in Baidu academic
[牛小伟]'s Articles
Bing Scholar
Similar articles in Bing Scholar
[牛小伟]'s Articles
Terms of Use
No data!
Social Bookmark/Share
No comment.
Items in the repository are protected by copyright, with all rights reserved, unless otherwise indicated.