本文選題：P53 + Jaggedl　； 參考：《復旦大學》2012年博士論文

【摘要】：眾所周知,高血壓可以引起心肌肥厚,起初的病理性心肌肥厚是心肌細胞適應壓力負荷的一種代償機制,但長時間的肥厚刺激,加之肥厚自身的有害性最終將導致心室的擴大、左室功能的減退和慢性心力衰竭的發(fā)生；目前來講,慢性心力衰竭在我們當今社會中仍然存在著較高的病死率,如何延緩心肌肥厚到心力衰竭的進展仍然是我們需要解決的話題。因此,對心肌肥厚發(fā)生發(fā)展機制的闡述具有其一定的必要性及現(xiàn)實性。以往的研究認為,在心肌肥厚發(fā)生發(fā)展的過程中,存在著心肌細胞和微血管數(shù)量之間的不平衡,使得心肌細胞相對缺氧,最終導致心肌肥厚發(fā)展到心力衰竭。盡管腎素-血管緊張素系統(tǒng),尤其是血管緊張素Ⅱ(AngⅡ)在心肌肥厚發(fā)生發(fā)展中的重要作用早已明確,伴隨著血管緊張素轉(zhuǎn)換酶抑制劑(ACEⅠ)及血管緊張素Ⅱ受體阻斷劑(ARBs)在臨床中的廣泛應用,AngⅡ在心肌肥厚治療中的地位亦被大多數(shù)學者所認可,但以往基于AngⅡ?qū)π呐K影響的研究主要集中在其對心肌細胞凋亡和心肌重構的探討上,其對心臟微血管的作用目前尚鮮有研究、作用機理亦尚未明確,因此本研究主要探討AngⅡ?qū)π呐K微血管的作用及其可能的分子機制,以期對心肌肥厚發(fā)生發(fā)展機理提供新的研究思路。 P53,腫瘤抑制因子,由393個氨基酸組成,是調(diào)節(jié)細胞周期、細胞衰老及凋亡的重要轉(zhuǎn)錄調(diào)控因子。生理條件下,p53蛋白在心臟組織中維持在較低的水平上,但在心肌細胞缺氧的條件下,p53蛋白被上調(diào)、左心室收縮功能障礙,但其并不直接導致心肌細胞死亡,而是通過抑制心臟血管的新生間接導致了心肌細胞死亡,進而影響了左室的收縮功能。當p53發(fā)生磷酸化之后,不但失去野生型p53抑制腫瘤增殖的作用,而且突變本身又使該基因具備癌基因功能。突變的p53蛋白與野生型p53蛋白相結合所形成的寡聚蛋白不能結合DNA,使得一些癌變基因轉(zhuǎn)錄失控最終導致腫瘤的發(fā)生。例如,p53可以被ATM, ATR和DNA-PK等在Ser15和Ser37位磷酸化,從而抑制p53的泛素化降解,促進p53的激活和積累。Chkl和Chk2可以磷酸化p53的Ser20,促進p53的四聚化,增強其穩(wěn)定性和活性。P53的Ser46磷酸化和其誘導細胞凋亡密切相關。P53的Ser392可以被CAK磷酸化,該位點磷酸化和p53的抑制生長功能及其與DNA結合并轉(zhuǎn)錄激活有關。2007年,日本Komuro團隊發(fā)表在Nature的研究發(fā)現(xiàn),壓力負荷下,p53累積,其下游保護性因子Hif-1a表達減少,使得心肌肥厚發(fā)展到心力衰竭,其在研究中提出此機制可能通過抑制心臟血管的新生間接導致心肌細胞死亡的這一假設,但尚未闡述p53對心肌微血管影響的具體機制。本文就此機理進行進一步的闡述。 Jagged1,Ⅰ型膜蛋白,Noth信號通路的一個配體,通過其Delta/Serrate/Lag2與Noth受體的EGF repeat結合參與諸如細胞表型、差異、分化、遷移、凋亡和血管新生等生理過程。盡管Jagged1在胚胎期動靜脈形成中所起的作用不可替代,但其在出生后的血管形成中并非必不可少。目前Jagged1在血管新生方面的研究主要集中在腫瘤領域的研究上,本實驗室先前的研究也主要集中在Jagged1在動脈粥樣硬化中動脈內(nèi)皮、動脈平滑肌的研究上,Jagged1在成年嚙齒類動物心肌微血管內(nèi)皮中的作用本實驗室及以外尚未有此方面的報道、其作用機制尚不是很明確。 鑒于此,我們假設Angll作用于心肌微血管內(nèi)皮細胞(CMVEC)上的AT1R,引起細胞膜上Notch配體-Jagged1的下調(diào),進而增加了p53在細胞漿中的蓄積,聯(lián)動保護性因子Hif-1a下調(diào),血管新生因子VEGF分泌減少,心臟血管新生障礙。本實驗共分為三個部分分別從離體和在體兩個層面上對這一設想進行闡述。 第一部分P53參與血管緊張素Ⅱ致心肌微血管內(nèi)皮細胞功能障礙的分子機制(離體實驗) 目的：P53在Angll致CMVEC功能障礙中的作用。 方法：1.心肌植塊法培養(yǎng)成年Wistar雄性大鼠的原代CMVEC,通過免疫熒光染色法鑒定細胞表面分子(vWF、CD31)的表達確定此種方法所培養(yǎng)的細胞為CMVEC,體外遷移實驗及體外管腔樣結構形成實驗明確CMVEC的體外血管新生能力。 2.10-6MAngⅡ干預第二或第三代CMVEC18hrs后,體外管腔樣結構形成實驗觀察其體外血管新生能力,同時采用western blotting方法觀察細胞中磷酸化p53(S392)、p53、Hif-1a及Jagged1的表達變化；realtime RT-PCR方法檢測AngⅡ干預后細胞中VEGF基因的變化；ELISA方法觀察CMVEC分泌到培養(yǎng)基中VEGF蛋白的變化。 3.在50μMpifithrin-a (PFT-a)阻斷p53的基礎上,AngⅡ干預CMVEC18hrs后,觀察CMVEC中上述指標(phospho-p53(S392)、p53、Hif-1a、Jagged1、gene/protein of VEGF)的變化(實驗所用方法同方法2)。 結果：1.心肌植塊法培養(yǎng)出的成年大鼠原代CMVEC具有很高的純度(約95%),此方法培養(yǎng)的CMVEC具備諸如體外遷移、體外血管新生的能力。 2.10-6M AngⅡ干預CMVEC后,上調(diào)了細胞核中p53的磷酸化,并使得胞漿中p53的蓄積增加,同時下調(diào)了細胞核中的Hif-1a蛋白,上調(diào)了細胞膜上Jagged1的表達、胞漿內(nèi)VEGF在RNA水平的表達,但減少了分泌到培養(yǎng)基中的VEGF蛋白。 3.50gM的PFT-a可以很好的阻斷p53的表達,在PFT-a阻斷p53的基礎上, AngⅡ干預CMVEC后,與單純AngⅡ干預組比較,CMVEC體外管腔樣結構形成能力增強,胞核中Hif-la表達上調(diào),分泌到培養(yǎng)基中的VEGF增加,胞膜上的Jagged1表達減少。 結論：10-6MAngⅡ干預CMVEC,引起CMVEC體外管腔樣結構形成障礙,這種損傷作用通過磷酸化細胞核中的p53,實現(xiàn)p53在胞漿中的蓄積,進而引起胞核中具有保護作用的Hif-1a下調(diào),血管新生因子VEGF分泌減少,從而損傷了CMVEC的體外血管新生能力。上調(diào)的Jagged1配體可能作為一種代償機制參與了AngⅡ致CMVEC的血管新生損傷作用。 第二部分在體實驗驗證p53參與血管緊張素Ⅱ致心肌微血管內(nèi)皮細胞功能損傷的分子機制 目的：對p53在AngⅡ致CMVEC功能障礙中的分子機理進行在體驗證。 方法：采用皮下埋藏微量泵的方法持續(xù)給予6-8周齡C57/BL6雄性小鼠200ng/kg/min AngⅡ,給藥時間為2周(預實驗建立給藥時間為1周、2周及4周的實驗動物模型)；在建立AngⅡ干預引起心肌肥厚模型的同時,設置p53抑制組,即在AngⅡ干預前一天腹腔注射3.0mg/kg PFT-a一次,隨后每間隔三天同劑量腹腔給藥一次,直至AngⅡ微量泵埋藏的第14天PFT-a給藥結束。AngⅡ給藥結束取材前,小動物心臟超聲測量小鼠左心室的肥厚程度,并用尾動脈壓測量裝置無創(chuàng)測量小鼠尾動脈壓力；取材時,稱量小鼠體重及其心臟重量,并在心臟的中1/2處將心臟橫斷為兩部分,將心尖所在部分立即投入液氮中備用于分子生物學實驗(western blotting, realtime RT-PCR)心底部放入10%中性福爾馬林溶液中,用做隨后的蘇木精-伊紅染色(HE)、免疫組織化學染色(CD31)。 結果：1.200ng/kg/min AngⅡ持續(xù)皮下給藥1周、2周、4周引起C57/BL6雄性小鼠心室壁的肥厚,以2周肥厚最為顯著；200ng/kg/min AngⅡ干預C57/BL6雄性小鼠2周后,CD31免疫組織化學染色顯示心臟微血管數(shù)量減少,同時有胞核中p53的磷酸化增加,胞漿中p53的蓄積增多,Hif-1a在胞核中的表達下調(diào),Jagged1在胞膜上的表達上調(diào),VEGF在組織中的表達增加。 2.3.0mg/kg PFT-a腹腔給藥,初次給藥時間為AngⅡ給藥前一天,后續(xù)每間隔三天給藥一次的方法能夠抑制p53的表達,并緩解AngⅡ給藥14天所致小鼠左心室的肥厚程度,與單純AngⅡ給藥14天組比較,此種處理增加了Hif-1a在心肌組織細胞核中的表達、減少了VEGF及Jagged1在心肌組織中的表達。 結論：200ng/kg/min AngⅡ干預C57/BL6雄性小鼠2周后,引起小鼠左心室肥厚,心臟微血管數(shù)量減少,且p53參與了此種損傷作用；抑制p53后,緩解了AngⅡ所致心肌的肥厚程度及心臟微血管數(shù)量的減少程度,與離體實驗p53參與了AngⅡ致CMVEC體外血管新生障礙這一實驗結果相符；但體實驗中,組織中增加的VEGF蛋白,可能是心肌細胞通過旁分泌對微血管障礙的一種代償機制。 第三部分Jagged1與p53在參與血管緊張素Ⅱ致心肌微血管內(nèi)皮細胞功能障礙機理中的關系 目的：分析Jagged1在AngⅡ所致CMVEC功能障礙中的角色及其與p53的關系。 方法：心肌植塊法培養(yǎng)成年Wistar雄性大鼠的原代CMVEC, anti-rat Jagged1siRNA預處置第二或第三代CMVEC后,10-6MAngⅡ干預CMVEC18hrs,體外管腔樣結構形成實驗觀察CMVEC的體外血管新生能力,western blotting方法觀察CMVEC中磷酸化p53(S392)、p53、Hif-1a的表達變化,realtime RT-PCR方法檢測AngⅡ干預后CMVEC中VEGF基因的變化；ELISA方法觀察培養(yǎng)基中分泌性蛋白-VEGF的變化。 結果：與單純AngⅡ干預組相比,anti-rat Jagged1siRNA預處置后、AngⅡ干預,CMVEC體外管腔樣結構形成能力增強,胞核中p53的磷酸化減少,但p53在胞漿中的累積、Hif-1a在胞核及胞漿中的表達、分泌到培養(yǎng)基中的VEGF均沒有統(tǒng)計學意義的變化。 結論：Jagged1在AngⅡ致CMVEC功能損傷作用中,既不是此處p53信號通路的上游分子,亦非其下游分子；而是作為另一個獨立信號分子參與此種損傷作用的。
[Abstract]:It is well known that hypertension can cause hypertrophy of the myocardium. At first the pathological myocardial hypertrophy is a compensatory mechanism for the stress load of the myocardium, but the prolonged hypertrophy of hypertrophy and the detrimental of hypertrophy will eventually lead to the enlargement of the ventricle, the decline of left ventricular function and the occurrence of chronic heart failure; at present, chronic heart is concerned. There is still a high mortality rate in our society, and how to delay the progress of cardiac hypertrophy to heart failure is still a topic we need to solve. Therefore, it is necessary and realistic to explain the mechanism of the development of cardiac hypertrophy. In the presence of imbalance between the number of cardiac myocytes and microvessels, myocardial cells are relatively anoxic and eventually lead to cardiac hypertrophy to heart failure. Although the role of the renin angiotensin system, especially angiotensin II (Ang II), in the development of cardiac hypertrophy has long been clear, accompanied by angiotensin conversion Enzyme inhibitor (ACE I) and angiotensin II receptor blocker (ARBs) are widely used in clinical practice. The status of Ang II in the treatment of myocardial hypertrophy is also recognized by most scholars. However, the previous studies based on the effect of Ang II on cardiac muscle cell withering and myocardial remodeling are mainly focused on the cardiac microvascular. In this study, the effect of Ang II on cardiac microvasculature and its possible molecular mechanism are discussed, so as to provide new research ideas for the mechanism of the development of cardiac hypertrophy.
P53, a tumor suppressor, consisting of 393 amino acids, is an important transcriptional regulator that regulates cell cycle, cell senescence and apoptosis. Under physiological conditions, the p53 protein is maintained at a lower level in the cardiac tissue, but the p53 protein is up-regulated and left ventricular systolic dysfunction under the condition of anoxia, but it does not directly lead to the dysfunction of the left ventricle. The death of the cardiac myocytes, but by inhibiting the birth of the heart blood vessels indirectly leads to the death of the cardiomyocytes, and then affects the contractile function of the left ventricle. When p53 is phosphorylated, it not only loses the role of the wild type p53 to inhibit the proliferation of the tumor, but also the mutation itself makes the gene have the function of the oncogene. The mutation of p53 protein and the wild type p53 The oligomeric protein formed by protein binding can not bind to DNA, making some cancerous gene transcriptional out of control eventually leading to the occurrence of tumors. For example, p53 can be phosphorylated by ATM, ATR and DNA-PK in Ser15 and Ser37 sites, thus inhibiting the ubiquitination of p53, promoting the activation of p53 and accumulating.Chkl and Chk2 phosphorylation p53. Four polymerization, enhancing its stability and active.P53 Ser46 phosphorylation and inducing cell apoptosis closely related to.P53 Ser392 can be phosphorylated by CAK, this site phosphorylation and p53 inhibition of growth function and DNA binding and transcriptional activation related.2007 years, Japanese Komuro team published in Nature research found under pressure load, p53 accumulation, The decrease of the protective factor Hif-1a in the lower reaches causes the development of myocardial hypertrophy to heart failure. In the study, it is suggested that this mechanism may inhibit the death of cardiac myocytes indirectly through the inhibition of cardiac angiogenesis, but the specific mechanism of the effect of p53 on myocardial microvessels has not been elaborated. This mechanism is further elaborated in this paper.
Jagged1, type I membrane protein, a ligand of the Noth signaling pathway, which combines its Delta/Serrate/Lag2 with the EGF repeat of the Noth receptor to participate in physiological processes such as cell phenotype, differentiation, differentiation, migration, apoptosis and angiogenesis. Although the role of Jagged1 in the embryonic stage of arteriovenous formation is irreplaceable, its vascular shape after birth Jagged1 is not essential. Current research on angiogenesis is mainly focused on the research in the field of tumor. Previous research in our laboratory is mainly focused on the role of Jagged1 in atherosclerotic artery endothelium, arterial smooth muscle research, and the role of Jagged1 in the myocardial microvascular endothelium of adult rodents. There has not been any report in this area and its mechanism is not very clear.
In view of this, we hypothesized that Angll acts on AT1R on the myocardial microvascular endothelial cells (CMVEC), causing the downregulation of the Notch ligand -Jagged1 on the cell membrane, thereby increasing the accumulation of p53 in the cytoplasm, the down regulation of the protective factor Hif-1a, the decrease of the secretion of angiogenesis factor VEGF, and the cardiac angiogenic disorder. The experiment was divided into three parts. Do not elaborate on this assumption from two levels: in vitro and in vivo.
Part I P53 involved in the molecular mechanism of angiotensin II induced dysfunction of myocardial microvascular endothelial cells (in vitro)
Objective: To investigate the role of P53 in CMVEC dysfunction induced by Angll.
Methods: the primary CMVEC of adult Wistar male rats was cultured by 1. myocardial explant method. The expression of vWF (CD31) was identified by immunofluorescence staining. The cells cultured in this method were CMVEC. The in vitro migration experiment and the formation of the tube like structure in vitro showed that the angiogenesis ability of CMVEC in vitro was confirmed.
After 2.10-6MAng II intervention for second or third generations of CMVEC18hrs, the angiogenesis in vitro was observed in vitro, and the expression of p53 (S392), p53, Hif-1a and Jagged1 in the cells were observed by Western blotting, and realtime RT-PCR square method was used to detect the changes of the genes in the cells after the intervention of Ang II. ISA method was used to observe the changes of CMVEC protein secreted into VEGF medium.
3. on the basis of 50 Mpifithrin-a (PFT-a) blocking p53 and Ang II intervention in CMVEC18hrs, the changes of the above indexes (phospho-p53 (S392), p53, Hif-1a, Jagged1, gene/protein) were observed by Ang II (the method used in the experiment and method 2).
Results: the primary CMVEC cultured in 1. myocardial explants had a high purity (about 95%). The CMVEC culture of this method had the ability to migrate in vitro and in vitro angiogenesis.
After the intervention of CMVEC, 2.10-6M Ang II increased the phosphorylation of p53 in the nucleus and increased the accumulation of p53 in the cytoplasm, down the Hif-1a protein in the nucleus, up the expression of Jagged1 on the cell membrane, and the expression of VEGF in the cytoplasm at RNA level, but reduced the VEGF protein secreted into the culture medium.
The PFT-a of 3.50gM can block the expression of p53 very well. On the basis of blocking p53 by PFT-a, Ang II interfered with CMVEC, and compared with the simple Ang II intervention group, the formation ability of CMVEC in vitro was enhanced, the expression of Hif-la in the nucleus was up, the VEGF increased in the medium, and the Jagged1 expression on the membrane decreased.
Conclusion: the intervention of 10-6MAng II to CMVEC causes the formation of CMVEC in vitro, which can cause the accumulation of p53 in the cytoplasm through the p53 in the phosphorylated nucleus, thereby causing a protective Hif-1a downregulation in the nucleus and reducing the secretion of the neovascularization factor VEGF, thereby damaging the angiogenesis of CMVEC in vitro. Up regulation of Jagged1 ligand may play a compensatory role in Ang II induced CMVEC angiogenesis.
The second part is in vivo experiments to verify the molecular mechanism of p53 involved in angiotensin II induced myocardial damage in microvascular endothelial cells.
Objective: To explore the molecular mechanism of p53 in Ang II - induced CMVEC dysfunction.
Methods: 6-8 weeks old C57/BL6 male mice 200ng/kg/min Ang II was continuously given by subcutaneous embedded micropump. The time of administration was 2 weeks (the experimental animal model was set up for 1 weeks, 2 and 4 weeks). The p53 inhibition group was set up at the same time when the Ang II intervention caused the hypertrophy of the myocardial hypertrophy, that is, the day before the intervention of Ang II. Intraperitoneal injection of 3.0mg/kg PFT-a once, followed by three days of the same dose of the same dose of intraperitoneal administration, until the fourteenth day of the Ang II micropump buried at the end of the PFT-a to end.Ang II, the small animal heart ultrasound measurement of the left ventricular hypertrophy of mice, and the tail artery pressure measurement device to measure the tail artery pressure in mice. Weighing the weight of the mice and the weight of the heart, and breaking the heart into two parts at the middle 1/2 of the heart, the part of the tip of the apex was immediately put into liquid nitrogen for use in the molecular biology experiment (Western blotting, realtime RT-PCR) to be placed in the 10% neutral formalin solution for subsequent hematoxylin eosin staining (HE) and immune tissue. Chemical staining (CD31).
Results: 1.200ng/kg/min Ang II sustained subcutaneous administration for 1 weeks, 2 weeks and 4 weeks to cause the hypertrophy of ventricular wall in C57/BL6 male mice, which was the most significant in 2 weeks. After 2 weeks of 200ng/kg/min Ang II intervention in C57/BL6 male mice, CD31 immuno histochemical staining showed that the number of cardiac microvessels decreased, and the phosphorylation of p53 in the nucleus increased and the cytoplasm was P5. The accumulation of Hif-1a increased, the expression of Jagged1 in the nucleus was down regulated, the expression of VEGF on the cell membrane was up-regulated, and the expression of VEGF in the tissue increased.
2.3.0mg/kg PFT-a was administered intraperitoneally for the first time before the time of Ang II administration. The subsequent administration of three days after each interval could inhibit the expression of p53 and alleviate the degree of left ventricular hypertrophy induced by Ang II Administration for 14 days. Compared with the 14 day group of pure Ang II administration, this treatment increased the table of Hif-1a in the nucleus of myocardial tissue. It reduced the expression of VEGF and Jagged1 in myocardium.
Conclusion: 200ng/kg/min Ang II interfered with C57/BL6 male mice for 2 weeks, causing the left ventricular hypertrophy and the decrease in the number of cardiac microvessels, and p53 participated in the injury. After the inhibition of p53, the degree of myocardial hypertrophy and the decrease in the number of cardiac microvessels caused by Ang II were relieved, and p53 in vitro participated in CMVEC in vitro blood of Ang II induced CMVEC in vitro. The results of this experiment are consistent with the experimental results, but in the body experiment, the increased VEGF protein in the tissue may be a compensatory mechanism for the microvascular obstruction by the paracrine of the cardiac myocytes.
The third part is the relationship between Jagged1 and p53 in the mechanism of dysfunction of myocardial microvascular endothelial cells induced by angiotensin II.
Objective: to analyze the role of Jagged1 in CMVEC dysfunction induced by Ang II and its relationship with p53.
Methods: the primary CMVEC of adult Wistar male rats was cultured by myocardial graft method. After anti-rat Jagged1siRNA was predisposed to second or third generations of CMVEC, 10-6MAng II intervened CMVEC18hrs. The angiogenesis of CMVEC in vitro was observed in vitro. Western blotting formula was used to observe the phosphorylation p53. Realtime RT-PCR method was used to detect the change of VEGF gene in CMVEC after Ang II intervention. ELISA method was used to observe the change of secretory protein -VEGF in the medium.
Results: compared with the simple Ang II intervention group, after the anti-rat Jagged1siRNA pretreatment, the Ang II intervention, the enhancement of the formation ability of CMVEC in vitro, the phosphorylation of p53 in the nucleus decreased, but the accumulation of p53 in the cytoplasm, the expression of Hif-1a in the nucleus and cytoplasm, and the secretion of VEGF in the culture medium were not statistically significant.
Conclusion: Jagged1 is not the upstream molecule of the p53 signaling pathway and the downstream molecules of the p53 signaling pathway, but is an independent signal molecule involved in this damage in the function of CMVEC damage induced by Ang II.

【學位授予單位】：復旦大學
【學位級別】：博士
【學位授予年份】：2012
【分類號】：R363

【共引文獻】

相關期刊論文 前9條

1 陳鵬;賀翔鴿;;體外培養(yǎng)大鼠視網(wǎng)膜神經(jīng)節(jié)細胞缺氧條件下HIF-1α動態(tài)表達及意義[J];重慶醫(yī)學;2006年15期

2 安金斗;梁芳;馮嵩;;右心衰竭幼齡大鼠B型鈉尿肽的變化及卡維地洛的干預作用[J];中國當代兒科雜志;2009年07期

3 馬芳芳;沈曉麗;;缺氧誘導因子-1在心血管疾病中的研究進展[J];國外醫(yī)學(老年醫(yī)學分冊);2008年03期

4 楊月霞;黃文新;;HIF-1在缺血缺氧性疾病中的研究進展[J];山東醫(yī)藥;2010年20期

5 劉磊;趙榮瑞;;低氧誘導因子-1及其在缺血性心臟疾病中的作用[J];生理科學進展;2006年03期

6 李曉;黃迪南;侯敢;;腫瘤血管生成調(diào)節(jié)因子的研究進展[J];生命科學;2007年02期

7 何金森;張學農(nóng);李仁杰;楊娟;李維;裘軍;姚穎;;新藥TJ0711對腎血管性高血壓大鼠的腎臟保護作用及機制[J];華中科技大學學報(醫(yī)學版);2012年02期

8 彭林林;吳強;;心血管疾病的膠原重塑及其干預研究[J];心血管病學進展;2007年02期

9 袁尉力;王緒凱;;普萘洛爾治療血管瘤分子生物學機制及其臨床應用研究進展[J];中國實用口腔科雜志;2012年02期

相關博士學位論文 前4條

1 鄒月芬;腫瘤三維細胞模型中應用RNAi抑制HIF-1和VEGF表達及與腫瘤照射之間的相關性研究[D];南京醫(yī)科大學;2010年

2 劉磊;關于心肌缺血/再灌注損傷及缺血預處理保護效應的進一步研究[D];山西醫(yī)科大學;2006年

3 趙曉民;血壓波動性增高致微循環(huán)異常和左心室肥厚及其機理的實驗研究[D];山東大學;2008年

4 馬利;乙酰半胱氨酸對糖尿病大鼠心肌缺血再灌注損傷的保護作用及其機制的研究[D];華中科技大學;2007年

相關碩士學位論文 前3條

1 丁玉龍;Wnt2b/β-catenin/c-myc信號途徑在小鼠胚胎心臟中的時空表達[D];桂林醫(yī)學院;2011年

2 胡賓;不同藥物對心力衰竭時腦鈉素的影響及機制研究[D];福建醫(yī)科大學;2006年

3 馬芳芳;HIF-1對心肌細胞缺氧/復氧損傷的保護作用的初步探討[D];福建醫(yī)科大學;2009年

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