本文選題：胃泌素 + 心臟缺血再灌注損傷�。� 參考：《第三軍醫(yī)大學(xué)》2015年碩士論文

【摘要】：一、研究背景缺血性心臟病(ischemic heart disease,IHD)嚴(yán)重威脅人類(lèi)健康安全,雖然醫(yī)療技術(shù)的發(fā)展使缺血的心肌盡早地實(shí)現(xiàn)了重建血運(yùn),拯救了許多缺血心肌,但同時(shí)帶來(lái)了心肌細(xì)胞致命的損傷,造成梗死面積的增大,發(fā)生缺血再灌注(ischemia/reperfusion,I/R)損傷。當(dāng)今世界已經(jīng)步入缺血再灌注治療的時(shí)代,如何減少缺血再灌注造成的心肌細(xì)胞損傷進(jìn)一步加重,已成為基礎(chǔ)研究者以及臨床醫(yī)生的研究熱點(diǎn)。I/R損傷發(fā)生的機(jī)制具有復(fù)雜性,各機(jī)制間相互影響彼此促進(jìn)。細(xì)胞凋亡和壞死是I/R損傷的重要的病理生理現(xiàn)象。研究發(fā)現(xiàn)減少心肌細(xì)胞凋亡可顯著減少細(xì)胞死亡,可顯著減少心肌梗死面積,因此減少心肌細(xì)胞凋亡對(duì)治療I/R損傷具有重要意義。細(xì)胞凋亡是一種程序性死亡,受多種基因和凋亡信號(hào)嚴(yán)格調(diào)控,在細(xì)胞凋亡基因及信號(hào)激活的同時(shí),機(jī)體的自我保護(hù)信號(hào)激活,如抑制凋亡的基因和促生存信號(hào)通路的激活(PI3K/Akt、ERK1/2、STAT3)。近年來(lái)對(duì)減少細(xì)胞凋亡的治療策略上進(jìn)行了大量的研究,取得了較為顯著的成果,如缺血前預(yù)處理、缺血后處理以及遠(yuǎn)端缺血預(yù)處理,這些治療措施中促生存途徑或多或少參與其中,并有許多藥物及治療處理應(yīng)用于臨床,如依達(dá)拉奉,但這些成果應(yīng)用于臨床卻受到安全性等很多因素的影響,目前仍感覺(jué)束手無(wú)策,因此急需要尋找出一些新的治療措施。既往發(fā)現(xiàn)飽食可減少心臟缺血再灌注造成大鼠心肌的損傷,同時(shí)也發(fā)現(xiàn)Akt被激活。我們知道受進(jìn)食影響最大的是胃腸道激素,其中胃泌素在進(jìn)食后循環(huán)中的濃度升高高于其他胃腸道激素,此外胃泌素具有抗調(diào)亡、營(yíng)養(yǎng)作用等生物活性,能激活機(jī)體的促生存途徑,包含RISK通路(PI3K/Akt、ERK1/2)與SAFE通路(STAT3)。因此推測(cè)胃泌素可能在飽食對(duì)心臟缺血再灌注損傷的保護(hù)中發(fā)揮作用,這種保護(hù)作用可能激活了心臟的促生存途徑(PI3K/Akt、ERK1/2、STAT3)而發(fā)揮的,以上問(wèn)題的解決可能為我們尋找出一種新的治療心臟缺血再灌注損傷的策略。二、研究目的明確胃泌素對(duì)心臟缺血再灌注損傷具有保護(hù)作用,并探討胃泌素通過(guò)何種機(jī)制在心臟缺血再灌注損傷中發(fā)揮保護(hù)作用。三、研究?jī)?nèi)容1.第一部分我們對(duì)胃泌素在在體心臟I/R損傷中的保護(hù)作用進(jìn)行研究,并對(duì)其機(jī)制進(jìn)行初步探討。將SD(Sprague Dawley)大鼠左前降支結(jié)扎,30min后剪開(kāi),制備在體的心臟I/R損傷模型,24小時(shí)后檢測(cè)心肌(LDH、Tn T-HSST)改變,TTC染色觀察心肌梗死面積,Tunel染色觀察心肌細(xì)胞凋亡,同時(shí)采用Western Blotting方法檢測(cè)凋亡蛋白Caspase-3、Akt、ERK1/2以及STAT3蛋白磷酸化表達(dá)水平,初步了解促生存途徑在其中的作用。2.第二部分我們對(duì)胃泌素在離體心臟I/R損傷的保護(hù)作用進(jìn)行研究,并對(duì)其作用機(jī)制進(jìn)行進(jìn)一步探討。采用Langendorff建立離體心臟缺血再灌注損傷模型(心臟整體缺血40min,再灌注60min,在缺血前給予20min的藥物干預(yù)),在該模型中去除了神經(jīng)體液因素以及胃泌素對(duì)冠脈流量的影響。左心室球囊通過(guò)壓力傳感器和橋式放大儀持續(xù)記錄心臟功能改變,收集缺血前以及再灌注60min時(shí)冠脈流出液檢測(cè)心肌酶(LDH、Tn T-HSST)改變,TTC染色檢測(cè)心肌梗死面積,TUNEL染色觀察和心肌細(xì)胞凋亡情況,采用Western Blotting方法檢測(cè)Caspase-3以及Akt、ERK1/2以及STAT3磷酸化水平,并應(yīng)用Akt、ERK1/2以及STAT3拮抗劑分別阻斷它們磷酸化改變,觀察胃泌素預(yù)處理對(duì)心臟缺血再灌注損傷的影響。四、研究結(jié)果1.在在體缺血再灌注損傷中,胃泌素預(yù)處理后24小時(shí)心肌酶(LDH、Tn T-HSST)釋放受到抑制,心梗面積縮小,心肌細(xì)胞凋亡下降,這些現(xiàn)象能被其受體拮抗劑CI 988所阻斷。應(yīng)用Western Blotting方法檢測(cè)發(fā)現(xiàn)胃泌素預(yù)處理促進(jìn)了Akt、ERK1/2以及STAT3蛋白磷酸化表達(dá)。2.在離體心臟缺血再灌注損傷中,胃泌素預(yù)處理可促進(jìn)缺血后心功能的恢復(fù)(LVDP、LVEDP、+dp/dtmax),減少心肌梗死面積,抑制心肌酶(LDH、Tn T-HSST)釋放以及減少心肌細(xì)胞的凋亡,這些作用能被其受體拮抗劑CI 988所阻斷。此外應(yīng)用Western Blotting方法檢測(cè)發(fā)現(xiàn)胃泌素預(yù)處理促進(jìn)了Akt、ERK1/2以及STAT3蛋白磷酸化表達(dá),并應(yīng)用Akt、ERK1/2以及STAT3拮抗劑分別阻斷它們磷酸化后觀察發(fā)現(xiàn)胃泌素對(duì)心臟I/R損傷的保護(hù)作用受到抑制,表現(xiàn)為心肌梗死面積增加,心肌酶釋放增多。五、結(jié)論胃泌素預(yù)處理對(duì)心臟I/R損傷具有保護(hù)作用。該作用可通過(guò)胃泌素受體激活促生存途徑即RISK信號(hào)通路(PI3K/Akt和ERK1/2)和SAFE信號(hào)通路(STAT3)來(lái)發(fā)揮。
[Abstract]:First, ischemic heart disease (IHD) is a serious threat to human health and safety. Although the development of medical technology makes the ischemic myocardium rebuild blood and save many ischemic myocardium, it also brings the fatal injury of myocardial cells, the increase of infarct size and the occurrence of ischemia reperfusion (ischem Ia/reperfusion, I/R) injury. The world has entered the era of ischemia reperfusion therapy. How to reduce the damage of myocardial cells caused by ischemia-reperfusion has become a research hotspot of basic researchers and clinicians. The mechanism of.I/R damage is complex, and the mechanisms of each mechanism interact to promote each other. And necrosis is an important pathophysiological phenomenon of I/R damage. It is found that reducing apoptosis can significantly reduce cell death and significantly reduce the area of myocardial infarction. Therefore, the reduction of myocardial apoptosis is of great significance in the treatment of I/R damage. At the same time that the apoptosis genes and signals are activated, the self protection signal of the body is activated, such as the inhibition of apoptosis gene and the activation of the survival signal pathway (PI3K/Akt, ERK1/2, STAT3). In recent years, a large number of studies have been carried out on the treatment strategies to reduce apoptosis, such as pre ischemic preconditioning and post ischemia. There are many drugs and treatment treatments used in clinical, such as edaravone, but these results are applied to a lot of factors such as safety, but they still feel helpless, so we need to find some new treatment urgently. Therapeutic measures. Previously found that full eating can reduce myocardial injury in rats with myocardial ischemia and reperfusion, and also found that Akt is activated. We know that gastrointestinal hormones are most affected by eating, and the concentration of gastrin in the circulation is higher than that of other gastrointestinal hormones, and gastrin has anti adjustment, nutrition, and so on. Activity, which activates the survival pathway of the body, including the RISK pathway (PI3K/Akt, ERK1/2) and the SAFE pathway (STAT3). Therefore, it is presumed that gastrin may play a role in the protection of cardiac ischemia reperfusion injury, which may activate the cardiac stimulating pathway (PI3K/Akt, ERK1/2, STAT3). The solution may find a new strategy for the treatment of ischemic reperfusion injury in the heart. Two. The purpose of this study is to clarify the protective effect of gastrin on cardiac ischemia reperfusion injury and to explore the mechanism of gastrin to protect the heart from ischemia reperfusion injury. Three. The first part of the study is to study the gastro secretion of the stomach. The protective effect of vegetarian on I/R injury in body heart was studied and its mechanism was preliminarily discussed. The left anterior descending branch of SD (Sprague Dawley) rats was ligated and 30min was cut open after 30min, and the I/R damage model of the heart was prepared. After 24 hours, the changes of myocardial (LDH, Tn T-HSST) were detected, the area of myocardial infarction was observed by TTC staining, and the myocardial cells were observed by Tunel staining. Apoptosis, and Western Blotting method was used to detect the phosphorylation of apoptotic protein Caspase-3, Akt, ERK1/2 and STAT3 protein, and the role of survival pathway in.2. second was preliminarily understood. The protective effect of gastrin on I/R injury in isolated heart was studied and the mechanism of its action was further explored. Ngendorff established an isolated myocardial ischemia reperfusion injury model (cardiac global ischemia 40min, reperfusion 60min, drug intervention for 20min before ischemia). In this model, the neurohumoral factors and the effect of gastrin on the coronary flow were removed. The left ventricular balloon was continuously recorded by pressure sensor and Bridge magnifying instrument. Changes of myocardial enzymes (LDH, Tn T-HSST) were detected before and before ischemia and reperfusion for 60min. TTC staining was used to detect myocardial infarction area, TUNEL staining and cardiomyocyte apoptosis. Western Blotting method was used to detect Caspase-3, Akt, ERK1/2, and STAT3 phosphorylation. The effects of gastrin preconditioning on cardiac ischemia reperfusion injury were observed respectively. Four. Results 1. in body ischemia reperfusion injury, the release of LDH (Tn T-HSST) was inhibited after 24 hours of gastrin preconditioning, the area of myocardial infarction was reduced, and the apoptosis of myocardial cells decreased. These phenomena could be antagonized by its receptor. CI 988 was blocked. Western Blotting method detected that gastrin pretreatment promoted Akt, ERK1/2, and STAT3 protein phosphorylation of.2. in ischemic reperfusion injury of isolated heart. Gastrin pretreatment could promote the recovery of cardiac function after ischemia (LVDP, LVEDP, +dp/ dtmax), decrease the area of myocardial infarction and inhibit myocardial enzyme SST) release and reduce the apoptosis of cardiac myocytes, which can be blocked by its receptor antagonist CI 988. In addition, the Western Blotting assay showed that gastrin pretreatment promoted the phosphorylation of Akt, ERK1/2 and STAT3 protein, and the gastric secreting was detected by Akt, ERK1/2 and STAT3 antagonists. The protective effect of peptide on cardiac I/R injury is inhibited, which shows an increase in infarct size and increased myocardial enzyme release. Five. Conclusion gastrin preconditioning has protective effect on cardiac I/R damage. This effect can be achieved through the activation of gastrin receptor (PI3K/Akt and ERK1/2) and SAFE signaling pathway (STAT3) through the activation of gastrin receptor.

【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類(lèi)號(hào)】：R541

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