發(fā)布時間：2017-12-31 07:11

  本文關鍵詞：SIRT1延緩小鼠下肢缺血后血流恢復的機制研究　出處：《河北醫(yī)科大學》2017年博士論文　論文類型：學位論文

  更多相關文章： 下肢缺血 缺氧 動脈生成 血管新生 SIRT1

【摘要】：正常組織功能的維持依賴于血管供氧和營養(yǎng)物質。組織缺血后血流恢復速度取決于血管新生和動脈生成過程。沉默信息調節(jié)因子1(silent information regulator 1,SIRT1)是一類依賴于NAD的去乙�；�,廣泛參與調節(jié)細胞生理活動和病理過程。有報道發(fā)現(xiàn)SIRT1通過抑制腫瘤血管新生而降低腫瘤生長,然而其對動脈生成的作用還不十分清楚,本研究旨在探尋SIRT1對動脈生成的調節(jié)及機制。目的:本研究以Sirt1轉基因(Sirt1-transgenic,Sirt1-Tg)小鼠和血管平滑肌細胞作為研究對象,通過建立下肢缺血模型和低氧誘導模型,試圖從體內外證實SIRT1在動脈生成中的作用,并探討其作用機制,以期為揭示缺血及缺血相關心血管疾病的發(fā)生機制提供研究證據。方法:利用Sirt1-Tg小鼠建立股動脈結扎下肢缺血模型,評價SIRT1與組織缺血后血流恢復的關系;應用SIRT1激動劑和抑制劑進一步驗證血流恢復與SIRT1活性的關系;利用免疫熒光染色分析缺血下肢腓腸肌毛細血管和小動脈密度;利用內皮細胞增殖、遷移、成管等體外實驗和基質膠塞、傷口愈合、視網膜鋪片等體內實驗,確定SIRT1活性和血管新生的關系;利用蛋白質免疫印跡、免疫共沉淀和免疫沉淀等技術,從蛋白質相互作用、蛋白質修飾的角度探討SIRT1對動脈生成的關鍵因子血小板衍生生長因子B(platelet-derived growth factor B,PDGFB)表達的調節(jié)及其分子機制。結果:1 SIRT1激活抑制小鼠下肢缺血后血流恢復1.1 Sirt1-Tg小鼠下肢缺血后血流恢復延遲為了探究SIRT1對組織缺血后血液灌注恢復的影響,小鼠進行股動脈結扎建立下肢缺血模型,采用激光散斑對比分析技術監(jiān)測下肢血流恢復情況。與WT(wild-type,WT)小鼠比較,Sirt1-Tg小鼠血流恢復明顯延遲,SIRT1抑制劑EX527腹腔注射使轉基因小鼠血流恢復明顯改善。1.2 SIRT1激活抑制小鼠下肢缺血后血流恢復復制小鼠下肢缺血模型,于不同時間點腹腔注射SIRT1激動劑白藜蘆醇(resveratrol,RSV)。結果顯示,延長用藥時間可加重血流恢復的延遲;反之,SIRT1抑制劑EX527可加快小鼠缺血下肢的血流恢復速度。結果表明,SIRT1激活抑制小鼠下肢缺血后血流恢復。1.3 Sirt1-Tg小鼠下肢缺血后腓腸肌動脈生成能力降低為了識別毛細血管和小動脈,在小鼠股動脈結扎后14天,使用CD31(內皮細胞標志物)和平滑肌(smooth muscle,SM)α-actin(平滑肌細胞標志物)抗體對腓腸肌組織切片進行免疫熒光染色。結果顯示,Sirt1-Tg小鼠下肢缺血側腓腸肌組織毛細血管密度(CD31陽性區(qū))和SMα-actin陽性的小動脈密度明顯低于WT小鼠,壁細胞(NG2陽性)的比例也顯著下降。結果表明,SIRT1激活抑制小鼠下肢缺血后動脈生成。2 SIRT1抑制血管新生2.1 SIRT1激活抑制內皮細胞增殖和成管功能為了探究SIRT1激活對內皮細胞功能的影響,低氧處理RSV或EX527預孵育的人臍靜脈內皮細胞(human umbilical vein endothelial cells,HUVEC)以及小鼠內皮細胞,結果顯示,SIRT1激活抑制兩種內皮細胞的增殖活性;SIRT1過表達抑制小鼠內皮細胞的遷移。為了進一步驗證SIRT1在血管新生中的作用,采用基質膠進行內皮細胞體外成管實驗,RSV預孵育的HUVEC成管能力降低。結果表明,SIRT1激活可抑制內皮細胞增殖、遷移和成管能力。2.2體內SIRT1過表達抑制血管新生為了探究體內SIRT1活性對血管新生的影響,將含有血管內皮生長因子A(vascular endothelial growth factor A,VEGFA)的基質膠植入WT和Sirt1-Tg小鼠皮下,發(fā)現(xiàn)Sirt1-Tg小鼠的基質膠塞中的血管擴張和壁細胞(NG2陽性)覆蓋降低。并且Sirt1-Tg小鼠的傷口愈合延遲。為進一步驗證SIRT1對血管新生的抑制作用,分析出生5天小鼠視網膜毛細血管,發(fā)現(xiàn)Sirt1-Tg小鼠視網膜毛細血管分支點的數目及血管長度明顯低于WT小鼠;用SIRT1激活劑RSV腹腔注射的新生WT小鼠,其視網膜血管新生受到明顯抑制,而應用SIRT1抑制劑EX527處理的小鼠其視網膜血管新生與未處理的對照組比較增強。結果顯示,激活SIRT1可抑制血管新生過程。2.3 SIRT1抑制內皮細胞Wnt/β-catenin信號通路和VEGFA表達VEGFA是Wnt/β-catenin信號通路的靶基因之一,在血管新生中發(fā)揮重要作用。小鼠股動脈結扎,Western blot檢測雙下肢腓腸肌,結果顯示,Sirt1-Tg小鼠VEGFA表達缺血側與對照側的比值明顯低于WT小鼠,β-catenin及其上游的DVL3表達水平降低,與VEGFA一致。RSV預孵育的HUVEC,低氧誘導后,VEGFA、β-catenin和DVL3的表達(低氧與常氧的比值)顯著低于對照組;反之,EX527預孵育以抑制SIRT1活性,三種蛋白的表達增加。結果表明,SIRT1通過抑制Wnt/β-catenin信號通路繼而下調VEGFA的表達。3 SIRT1通過抑制低氧誘導的血管平滑肌細胞PDGFB表達阻礙動脈生成3.1 SIRT1抑制缺血誘導的PDGFB表達為了探究Sirt1-Tg小鼠下肢缺血后動脈生成障礙的分子機制,檢測PDGFB表達和ERK活化。Western blot分析顯示,Sirt1-Tg小鼠腓腸肌PDGFB表達缺血側/對照側比值明顯低于WT小鼠,同時p-ERK的比值也顯著降低;定量RT-PCR顯示,Sirt1-Tg小鼠腓腸肌PDGFB m RNA表達的比值(缺血側/對照側)較WT小鼠顯著下降。然而,Sirt1-Tg小鼠腹腔注射EX527則可逆轉這一現(xiàn)象。說明抑制SIRT1活性可促進缺血誘導的PDGFB表達和信號轉導活性。3.2 SIRT1抑制低氧誘導因子1α(hypoxia-inducible factor 1α,HIF-1α)介導的PDGFB基因轉錄HIF-1α參與動脈生成。為探究SIRT1抑制PDGFB表達的機制,低氧處理WT小鼠VSMC。結果顯示,HIF-1α表達與PDGFB蛋白和m RNA水平成正相關。為了進一步確定HIF-1α參與缺血誘導的PDGFB表達調節(jié),基于PDGFB基因中含有HIF-1α結合位點進行Ch IP分析。結果顯示,HIF-1α與PDGFB增強子序列(HBS1)結合活性在低氧誘導后明顯增加;構建包含HIF-1α結合位點的的熒光素酶報告基因質粒,轉染293T細胞,結果顯示,低氧誘導的熒光素酶表達活性升高。過表達SIRT1,則抑制HIF-1α與PDGFB基因HBS1增強子的結合;激活SIRT1(RSV預孵育),同樣抑制低氧誘導的熒光素酶報告基因活性;反之,抑制SIRT1活性(EX527預孵育)則促進低氧誘導的熒光素酶表達。結果表明,SIRT1抑制低氧誘導的HIF1α激活及其介導的PDGFB基因轉錄。3.3 SIRT1介導HIF1α的去乙�；Щ顬榱颂骄縎IRT1抑制HIF-1α介導的PDGFB表達的分子機制,免疫沉淀分析HIF-1α乙�；�。結果顯示,低氧可誘導VSMC中HIF-1α乙�；�;過表達或激活SIRT1可降低低氧誘導的HIF-1α乙�；�,同時PDGFB蛋白表達降低;反之用EX527抑制SIRT1活性則可逆轉HIF-1α的去乙�；蚉DGFB表達的降低。為了進一步驗證SIRT1介導HIF-1α的去乙酰化失活,進行免疫共沉淀檢測SIRT1與HIF-1α的相互作用。結果顯示,低氧時SIRT1與HIF-1α的相互作用減弱;過表達或激活SIRT1,二者的相互作用增強,而抑制SIRT1活性二者的相互作用減弱。結果表明,SIRT1介導的HIF-1α去乙�；Щ羁梢种迫毖跽T導的PDGFB基因表達。結論:1 SIRT1激活抑制小鼠下肢缺血后動脈生成,導致下肢血流恢復延遲。2 SIRT1通過抑制Wnt/β-catenin信號通路而下調VEGFA表達,進而抑制內皮細胞增殖和血管新生。3 SIRT1介導的HIF-1α去乙�；Щ羁梢种迫毖跽T導的PDGFB表達和動脈生成。
[Abstract]:To maintain normal tissue function depends on the blood oxygen and nutrition after ischemia. Blood flow recovery rate depends on angiogenesis and arteriogenesis. Silent information regulator 1 (silent information 1 regulator, SIRT1) is a class of histone deacetylase NAD dependent, widely involved in the regulation of cell physiological activities and pathological processes. SIRT1 through the inhibition of tumor angiogenesis and reduce tumor growth reported, however the artery formation is not clear, the purpose of this study was to explore the effect of SIRT1 on arterial and mechanism of the formation. Objective: in this study, Sirt1 transgenic (Sirt1-transgenic, Sirt1-Tg) and vascular smooth muscle cells of mice as the research object, and through the establishment of model hypoxia induced lower limb ischemia model, trying to confirm the role of SIRT1 in the artery in the generation from outside the body, and to explore its mechanism, in order to reveal the ischemia and lack of Study on the mechanism of blood provide evidence of cardiovascular diseases. Methods: the Sirt1-Tg mice femoral artery ligation model of lower limb ischemia, SIRT1 after ischemia and evaluate the relationship between blood flow recovery; application of SIRT1 agonists and antagonists to further verify the recovery of blood flow relationship with SIRT1 activity; dyeing analysis of ischemic gastrocnemius muscle capillary and arteriolar density by immunofluorescence use; endothelial cell proliferation, migration, tube formation in vitro assay and Matrigel plugs, wound healing, the retinas of mice, to determine the relationship between SIRT1 activity and angiogenesis; using Western blotting, immunoprecipitation and immunoprecipitation, from protein interaction, protein modification of key factor platelet the formation of arterial SIRT1 derived growth factor B (platelet-derived growth factor B, PDGFB) expression and its molecular regulation The mechanism of activation of SIRT1. Results: 1 the recovery of blood flow of mice 1.1 Sirt1-Tg after ischemia of lower limb blood flow recovery delay in order to explore the effects of SIRT1 on blood perfusion recovery after ischemia inhibited limb ischemia in mice, mice model of lower limb ischemia femoral artery ligation, using laser speckle contrast analysis technology to monitor the recovery of lower limb blood flow (wild-type, and WT. WT) mice, Sirt1-Tg mice blood recovery was significantly delayed, intraperitoneal injection of EX527 SIRT1 inhibitor restored to significantly improve.1.2 SIRT1 inhibiting activation of lower extremity ischemia mice after restoration of blood flow replication of lower limb ischemia mouse model of transgenic mice blood flow at different time points by intraperitoneal injection of SIRT1 agonist resveratrol (resveratrol, RSV). The results showed that prolonged treatment delay time can increase the recovery of blood flow; on the other hand, the SIRT1 inhibitor EX527 can accelerate the recovery of blood flow velocity of lower limb ischemia in mice. Results That SIRT1 inhibiting activation of lower extremity ischemia mice after restoration of blood flow.1.3 Sirt1-Tg mice gastrocnemius artery ischemia of lower extremity after generation capacity is reduced in order to identify the capillaries and small arteries, femoral artery ligation in mice after 14 days, the use of CD31 (endothelial cell marker) and smooth muscle (smooth muscle, SM) -actin (alpha smooth muscle cell markers) antibody immunofluorescence staining of tissue sections of gastrocnemius. The results showed that the capillary density in Sirt1-Tg mouse hindlimb ischemia side gastrocnemius muscle (positive CD31) and SM alpha -actin positive arteriolar density was significantly lower than that in WT mice, parietal cells (NG2 positive) proportion decreased significantly. The results showed that the activation of SIRT1 inhibited mice after ischemia of lower extremity artery formation.2 SIRT1 inhibits angiogenesis 2.1 activation of SIRT1 inhibited endothelial cell proliferation and tube function in order to explore the SIRT1 on endothelial cell activation function the influence of hypoxia treatment RSV Or EX527 preincubation of human umbilical vein endothelial cells (human umbilical vein endothelial cells, HUVEC) and the results showed that SIRT1 of endothelial cells in mice, inhibit the activation of two kinds of endothelial cell proliferation activity; overexpression of SIRT1 inhibits the migration of endothelial cells in mice. In order to further verify the role of SIRT1 in angiogenesis, using matrix glue in vitro endothelial cell tube formation, RSV preincubation of HUVEC tube into reduced ability. The results showed that SIRT1 activation can inhibit endothelial cell proliferation, migration and tube formation of.2.2 in vivo overexpression of SIRT1 inhibits angiogenesis in vivo in order to explore the effect of SIRT1 activity on angiogenesis, including vascular endothelial growth factor A (vascular endothelial growth factor A, VEGFA) of the Matrigel implantation of WT and Sirt1-Tg mice, found that vascular dilatation and wall plug stromal cells in Sirt1-Tg mice (NG2 positive) cover down Low. Sirt1-Tg mice and delayed wound healing. Inhibition of angiogenesis to validate the SIRT1 analysis, was born 5 days of retinal capillary in mice, found that the number and length of vessels of Sirt1-Tg mouse retinal capillary branch points was significantly lower than that of WT mice; activator RSV intraperitoneal injection with SIRT1 WT newborn mice, the retinal neovascularization is obvious comparison and application of SIRT1 enhanced inhibition, inhibitor EX527 in mice retinal neovascularization and the untreated control group. The results showed that the activation of SIRT1 can inhibit the angiogenesis of.2.3 SIRT1 inhibition of endothelial cell Wnt/ beta -catenin signaling pathway and the expression of VEGFA VEGFA is one of the target genes of Wnt/ beta -catenin signaling pathway play an important role in angiogenesis. In mice. Femoral artery ligation, Western blot detection of double gastrocnemius muscle, results showed that Sirt1-Tg VEGFA expression in ischemic mice The ratio of side and the control side was significantly lower than that in WT mice, the expression levels of beta -catenin and its upstream DVL3 decreased, consistent with the VEGFA.RSV preincubation of HUVEC induced by hypoxia, VEGFA, -catenin and DVL3 expression of beta (ratio of hypoxia and normoxia) was significantly lower than the control group; on the other hand, preincubation of EX527 to inhibit the activity of SIRT1, increase the expression of the three proteins. The results showed that the.3 of SIRT1 by PDGFB in vascular smooth muscle cells inhibits hypoxia induced expression of SIRT1 3.1 generation block arterial inhibition of ischemia induced PDGFB expression in order to explore the molecular mechanism of Sirt1-Tg mice after hindlimb ischemia artery dyspoietic SIRT1 expression by inhibiting Wnt/ beta -catenin signaling pathway and down-regulation of VEGFA. To detect the expression of PDGFB and activation of ERK.Western blot analysis showed that the expression of Sirt1-Tg in mouse gastrocnemius PDGFB ischemic / control side were significantly lower than those in WT mice, the ratio of p-ERK decreased significantly at the same time; Quantitative RT-PCR showed that the ratio of Sirt1-Tg mice gastrocnemius PDGFB m expression of RNA (ischemic side / control side) was significantly higher than that of WT mice decreased. However, Sirt1-Tg mice by intraperitoneal injection of EX527 can reverse this phenomenon. It inhibited the activity of SIRT1 can promote PDGFB expression and signal transduction of.3.2 activity of ischemia induced SIRT1 inhibition of hypoxia inducible factor 1 alpha (hypoxia-inducible alpha factor alpha 1, HIF-1) mediated PDGFB gene transcription in HIF-1 alpha generation. To explore the mechanism of SIRT1 artery to inhibit the expression of PDGFB, hypoxia treated WT mice VSMC. results showed that HIF-1 expression was positively correlated with PDGFB protein and m RNA level. In order to further determine the HIF-1 alpha is involved in ischemia induced PDGFB expression regulation of PDGFB gene containing HIF-1 alpha binding sites were Ch based on IP analysis. The results showed that HIF-1 alpha and PDGFB enhancer (HBS1) binding activity in hypoxia increased significantly after induction; construct HIF-1 alpha binding sites of luciferase reporter plasmid, the transfected 293T cells showed that hypoxia induced expression of luciferase activity increased. Overexpression of SIRT1 combined inhibition of HIF-1 alpha and PDGFB HBS1 gene enhancer; activated SIRT1 (RSV preincubation), also inhibited luciferase activity induced by hypoxia; conversely, inhibition the activity of SIRT1 (EX527 preincubation) promotes hypoxia induced luciferase expression. The results showed that SIRT1 inhibited hypoxia induced activation of HIF1 alpha and PDGFB mediated by.3.3 gene transcription mediated by SIRT1 HIF1 alpha to acetylation in order to explore the molecular mechanism of inactivation of SIRT1 expression inhibition of HIF-1 mediated by PDGFB, immunoprecipitation analysis of HIF-1 alpha acetylation level. The results showed that hypoxia VSMC HIF-1 acetylation induced by alpha; overexpression or activation of SIRT1 can reduce hypoxia induced HIF-1 alpha acetylation, and decreased expression of PDGFB protein; reverse The use of EX527 to inhibit the activity of SIRT1 decreased acetylation and PDGFB expression of reversed HIF-1 alpha. In order to verify the SIRT1 mediated deacetylation of HIF-1 alpha inactivation, interaction of immunoprecipitation to detect SIRT1 and HIF-1 alpha. The results showed that hypoxia interaction between SIRT1 and HIF-1 alpha had weakened; the expression or activation of SIRT1, enhance the interaction between the two, and inhibit the interaction of SIRT1 two activity decreased. The results showed that the expression of PDGFB gene SIRT1 mediated HIF-1 deacetylation alpha inactivation can inhibit hypoxia induced activation of SIRT1 1. Conclusion: inhibition of lower limb ischemia in mice after artery formation, resulting in lower limb blood flow recovery delay.2 SIRT1 Wnt/ by inhibiting the -catenin signaling pathway and down-regulation of VEGFA expression, PDGFB expression and inhibit arterial endothelial cell proliferation and angiogenesis of.3 SIRT1 mediated HIF-1 alpha deacetylation can inhibit hypoxia induced inactivation of students .

【學位授予單位】：河北醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R54

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