本文選題：普羅布考 + 血管功能　； 參考：《中南大學(xué)》2014年博士論文

【摘要】：第一部分Probucol通過促進(jìn)eNOS活化保護(hù)H202誘導(dǎo)的內(nèi)皮依賴性血管舒張功能的降低 背景 普羅布考(Probucol, PB,又名丙丁酚)是一種人工合成的抗氧化劑。它作為一種雙酚類化合物,具有降低膽固醇、抗氧化、抗炎及抗動(dòng)脈粥樣硬化等多重作用,最初是作為降脂藥物應(yīng)用于臨床。臨床試驗(yàn)、動(dòng)物及體外實(shí)驗(yàn)發(fā)現(xiàn)probucol對(duì)某些病理改變下血管收縮舒張功能有直接作用,并證實(shí)其對(duì)血管功能的作用獨(dú)立于其降脂效果。氧化應(yīng)激是高血壓、動(dòng)脈粥樣硬化等心血管疾病的發(fā)病機(jī)制,氧化應(yīng)激通過作用于血管細(xì)胞,從而影響血管的收縮和舒張活性。而probucol的抗氧化性不僅表現(xiàn)在抑制脂質(zhì)(如低密度脂蛋白LDL)的氧化,也可以清除血液和組織中自由基,這提示probucol的抗氧化作用是否是其影響氧化應(yīng)激下血管功能改變的機(jī)制,以及是否對(duì)于心血管疾病的血管舒縮功能有保護(hù)作用。 血管內(nèi)皮是維持血管穩(wěn)態(tài)的主要調(diào)節(jié)者。已知內(nèi)皮細(xì)胞是血管收縮和舒張活性的重要組成部分,而內(nèi)皮功能障礙可以導(dǎo)致血管收縮及舒張功能平衡紊亂,血壓調(diào)節(jié)異常；此外內(nèi)皮細(xì)胞受損還可以導(dǎo)致血液細(xì)胞黏附增加,炎癥細(xì)胞浸潤血管以及促-抗凝血平衡失調(diào)等。臨床試驗(yàn)證實(shí)內(nèi)皮細(xì)胞功能障礙是心血管事件的危險(xiǎn)因素之一。而氧化應(yīng)激對(duì)血管性疾病的發(fā)生發(fā)展有促進(jìn)作用,活性氧族(reactive oxygen species, ROS)首先破壞內(nèi)皮細(xì)胞功能,影響內(nèi)皮的調(diào)壓、抗凝及內(nèi)分泌合成功能,這可能是動(dòng)脈粥樣硬化、高血壓、糖尿病等血管病變的原因之一。 目的 Probucol多效性作用機(jī)制尚不明確,而且probucol對(duì)血管舒縮功能的作用仍有爭(zhēng)議。本實(shí)驗(yàn)為了探討probucol對(duì)血管收縮及舒張功能的作用；并根據(jù)probucol的抗氧化特性進(jìn)一步探討,在H2O2誘導(dǎo)氧化損傷基礎(chǔ)下probucol對(duì)血管舒張功能的影響及作用機(jī)制。 方法 使用大鼠離體胸主動(dòng)脈血管環(huán)構(gòu)建H2O2損傷內(nèi)皮依賴性血管舒張功能的模型。(1)使用myograph技術(shù)研究離體血管環(huán)的收縮及舒張功能,使用高鉀(KCl)、去氧腎上腺素(PE)分別誘導(dǎo)血管收縮反應(yīng),乙酰膽堿(ACh)、硝普鈉(SNP)誘導(dǎo)血管舒張反應(yīng)(內(nèi)皮依賴性和非內(nèi)皮依賴性)。觀察血管在H2O2的持續(xù)作用下,血管基礎(chǔ)功能的變化情況。(2)在H2O2作用的基礎(chǔ)上,myograph檢測(cè)PB干預(yù)處理對(duì)血管功能的影響,并且使用western blot技術(shù)檢測(cè)干預(yù)后血管環(huán)內(nèi)皮特異性一氧化氮合酶(eNOS)蛋白的表達(dá)情況,探討PB對(duì)血管環(huán)舒張功能的作用是否是通過影響內(nèi)皮細(xì)胞eNOS的產(chǎn)生來實(shí)現(xiàn)的。(3)使用血管環(huán)組織培養(yǎng)技術(shù)進(jìn)一步探討PB對(duì)不良應(yīng)激下內(nèi)皮依賴性舒張功能的作用,myograph檢測(cè)培養(yǎng)后血管環(huán)活性的改變。 建立apoE-/-動(dòng)脈粥樣硬化小鼠模型,在體實(shí)驗(yàn)研究在動(dòng)脈粥樣硬化疾病血管損傷基礎(chǔ)上PB對(duì)血管舒張功能的影響,及其對(duì)血脂代謝的作用與血管功能改變的相關(guān)性 培養(yǎng)原代人臍靜脈內(nèi)皮細(xì)胞(HUVECs),同樣在體外實(shí)驗(yàn)中建立H202損傷血管內(nèi)皮功能的模型,主要進(jìn)行以下實(shí)驗(yàn)：(1) HUVECs的培養(yǎng)及鑒定；(2)實(shí)時(shí)熒光定量RT-qPCR及western blot檢測(cè)PB對(duì)內(nèi)皮細(xì)胞eNOS mRNA、蛋白表達(dá)水平的影響,對(duì)eNOS活化程度的影響；(2)在H2O2損傷情況下,PB對(duì)內(nèi)皮細(xì)胞eNOS表達(dá)水平的作用,探討PB是否通過影響eNOS表達(dá)來保護(hù)內(nèi)皮細(xì)胞功能；(3)免疫熒光顯微鏡觀察以及熒光定量檢測(cè)HUVEC在H2O2誘導(dǎo)氧化損傷時(shí)NO的生成,以及PB對(duì)NO產(chǎn)生的作用,探討PB是否能激活eNOS-NO生成途徑達(dá)到保護(hù)內(nèi)皮介導(dǎo)舒張功能的作用。 結(jié)果 1.H2O2在一定濃度及作用時(shí)間下可以誘導(dǎo)氧化損傷,選擇性抑制大鼠離體胸主動(dòng)脈血管環(huán)ACh誘導(dǎo)的內(nèi)皮依賴性舒張功能,對(duì)血管收縮功能無明顯作用。高濃度或長時(shí)間H2O2作用可以造成不可逆的血管收縮及舒張功能的喪失。 2.在H2O2誘導(dǎo)的氧化應(yīng)激下,PB (5-20μM)保護(hù)大鼠及小鼠離體胸主動(dòng)脈血管環(huán)ACh誘導(dǎo)的內(nèi)皮依賴性血管舒張功能。 3.PB通過抑制H2O2誘導(dǎo)的離體血管環(huán)eNOS活性下降,保護(hù)內(nèi)皮細(xì)胞功能,但對(duì)收縮功能無顯著作用。 4.在組織培養(yǎng)過程中,PB對(duì)大鼠胸主動(dòng)脈血管環(huán)的內(nèi)皮依賴性舒張功能也有保護(hù)作用。 5.在apoE-/-動(dòng)脈粥樣硬化小鼠模型中,PB可以保護(hù)小鼠主動(dòng)脈內(nèi)皮依賴性舒張功能,且該作用與其降脂效果無關(guān)。 6.PB可以提高人臍靜脈內(nèi)皮細(xì)胞中p-eNOS/eNOS比值,促進(jìn)eNOS的磷酸化程度(Ser-1177),激活eNOS氧化活性；H2O2抑制eNOS總蛋白表達(dá)水平,PB保護(hù)H2O2誘導(dǎo)氧化損傷情況下eNOS的磷酸化水平。 7.PB促進(jìn)人臍靜脈內(nèi)皮細(xì)胞中eNOS活化的產(chǎn)物NO的產(chǎn)生。 結(jié)論 PB對(duì)于H2O2誘導(dǎo)的內(nèi)皮依賴性舒張功能障礙有保護(hù)作用,其機(jī)制可能是PB通過促進(jìn)eNOS磷酸化,激活eNOS氧化酶活性,從而促進(jìn)NO的生成有關(guān)。 第二部分普羅布考對(duì)平滑肌細(xì)胞表型的作用及其與平滑肌細(xì)胞增殖遷移的關(guān)系 背景 血管平滑肌細(xì)胞VSMCs作為血管壁的重要構(gòu)成部分,其功能的異常與心血管疾病有密切關(guān)系。VSMCs增殖及合成作用參與動(dòng)脈粥樣硬化斑塊的形成,平滑肌細(xì)胞源性泡沫細(xì)胞是斑塊的細(xì)胞成分之一。傳統(tǒng)觀點(diǎn)認(rèn)為平滑肌細(xì)胞具有收縮型及合成型兩種表型,而病理改變與合成/增殖型有關(guān)。而新觀點(diǎn)認(rèn)為病變血管周圍或血液來源的干細(xì)胞才是斑塊形成的主要細(xì)胞來源,它們擁有部分SMC表型標(biāo)記,但不同于普通平滑肌細(xì)胞的功能,擁有更多干細(xì)胞的特性,因此提出這種多能干細(xì)胞性的平滑肌細(xì)胞是SMC參與血管病理改變的基礎(chǔ)。因此SMC干細(xì)胞活性增加與血管病灶處SMC增殖或合成作用有關(guān),主要以高分化平滑肌細(xì)胞收縮蛋白的降低(包括α-actin、SM22、calponin及SM-MHC (SM1、SM2))以及干細(xì)胞標(biāo)志升高。 動(dòng)物實(shí)驗(yàn)發(fā)現(xiàn)probucol可以抑制家兔主動(dòng)脈球囊擴(kuò)張損傷后血管再狹窄,抑制平滑肌細(xì)胞增殖和遷移,抑制內(nèi)膜增厚、管腔變窄,并且改善血管重構(gòu)。因此我們從SMC對(duì)血管疾病的作用機(jī)理和表型變化出發(fā),探討PB的對(duì)心血管疾病的保護(hù)作用是否與SMC表型有關(guān),及其對(duì)SMC增殖遷移的作用。 目的 探索probucol對(duì)平滑肌細(xì)胞增殖及遷移的作用以及該作用是否與平滑肌細(xì)胞的表型變化有關(guān)。 方法 (1)使用組織塊貼壁法提取并培養(yǎng)原代大鼠的血管平滑肌細(xì)胞,使用免疫熒光染色鑒定原代VSMCs。觀察原代細(xì)胞提取和培養(yǎng)過程中細(xì)胞形態(tài)及增殖分化過程,使用PB干預(yù)血管組織塊以觀察細(xì)胞從組織塊原位的遷出情況；并且在細(xì)胞接種過程中直接計(jì)數(shù)PB對(duì)細(xì)胞增殖數(shù)目的影響。 (2)使用Transwell細(xì)胞遷移實(shí)驗(yàn)檢測(cè)PB及oxLDL對(duì)VSMCs的遷移影響 (3)采用RT-qPCR技術(shù)、western-blot技術(shù)研究VSMCs中表型相關(guān)蛋白α-actin、干細(xì)胞標(biāo)志Sox-10的表達(dá)變化,以及平滑肌細(xì)胞轉(zhuǎn)錄激活因子myocardin的表達(dá)改變情況。 結(jié)果(1) α-actin+SM22+Sox-10-是高分化VSMCs的表型特征； (2)PB單獨(dú)作用抑制VSMCs干細(xì)胞標(biāo)志Sox-10的表達(dá),也抑制myocardin、SM22表達(dá),但不影響收縮蛋白α-actin的表達(dá)。H202誘導(dǎo)氧化應(yīng)激促進(jìn)Sox-10表達(dá)并下調(diào)myocardin表達(dá),而PB可以部分逆轉(zhuǎn)該變化,即H2O2作用基礎(chǔ)上PB抑制Sox-10,促進(jìn)myocardin表達(dá)。 (3)PB抑制VSMCs從組織內(nèi)遷移以及在體外培養(yǎng)過程中的遷移及增殖速率； 結(jié)論 在體外研究中發(fā)現(xiàn)PB可以抑制大鼠VSMCs的遷移及增殖,其機(jī)制可能與PB抑制平滑肌干細(xì)胞的分化及運(yùn)動(dòng)能力有關(guān)。
[Abstract]:The first part of Probucol protects H202 induced endothelium-dependent vasodilation by promoting eNOS activation.
background
Probucol (PB, also known proproopol) is a synthetic antioxidant. It is a kind of bisphenol compound, which has multiple effects on lowering cholesterol, antioxidation, anti-inflammatory and anti atherosclerosis. It was first used as a lipid lowering drug in clinical practice. In clinical trials, animal and in vitro experiments found probucol to some pathology. The function of vasoconstriction and vasodilatation has a direct effect, and it is confirmed that its effect on vascular function is independent of its lipid lowering effect. Oxidative stress is the pathogenesis of cardiovascular diseases such as hypertension and atherosclerosis. Oxidative stress acts on vascular cells and thus affects vasoconstrictor and diastolic activity of blood vessels. The antioxidant activity of probucol is not Only the inhibition of lipid (such as low density lipoprotein LDL) oxidation can also remove free radicals in the blood and tissue, which suggests that the antioxidant effect of probucol is the mechanism that affects the changes in vascular function under oxidative stress, and whether it has protective effects on vascular systolic function in cardiovascular disease.
Vascular endothelium is the main regulator for the maintenance of vascular homeostasis. Known endothelial cells are an important component of vasoconstriction and diastolic activity. Endothelial dysfunction can lead to a balance disorder of vasoconstriction and diastolic function, abnormal blood pressure regulation, and endothelial cell damage can also lead to increased blood cell adhesion and inflammatory cell infiltration. Blood vessels and anticoagulant balance disorders. Clinical trials have confirmed that endothelial dysfunction is one of the risk factors for cardiovascular events. Oxidative stress can promote the development of vascular diseases. Reactive oxygen species (ROS) first destroys endothelial cell function, affects endothelial pressure, anticoagulant and internal components. Secretory function, which may be one of the causes of atherosclerosis, hypertension, diabetes and other vascular diseases.
objective
The mechanism of Probucol's pleiotropic action is still unclear, and the effect of probucol on vasomotor function is still controversial. This experiment is to explore the effect of probucol on vasoconstriction and diastolic function, and further explore the effect of probucol on vasodilatation based on H2O2 induced oxidative damage and the effect of probucol on vasodilatation. Use the mechanism.
Method
A model of endothelium-dependent vasodilatation of H2O2 injury was constructed using the isolated thoracic aorta ring of rats. (1) the systolic and diastolic function of the isolated vascular rings was studied by myograph technique. The vasoconstrictor response was induced by high potassium (KCl), deoxyadrenaline (PE), acetylcholine (ACh), and sodium nitroprusside (SNP) induced vasodilatation. Skin dependence and non endothelium-dependent). Observe the changes of vascular basic function under the continuous action of H2O2. (2) on the basis of H2O2 action, myograph detected the effect of PB intervention on vascular function, and the expression of endothelial specific nitric oxide synthase (eNOS) protein expression after intervention using Western blot technique. To investigate whether the effect of PB on vascular ring diastolic function is achieved by affecting the production of eNOS in endothelial cells. (3) the effect of PB on endothelium dependent vasodilatation under adverse stress, and the changes of vascular ring activity after myograph were detected by vascular ring tissue culture.
The effect of PB on vasodilatation on the basis of vascular injury of atherosclerotic disease, and the correlation between the role of blood lipid metabolism and vascular function change in the experimental study of atherosclerotic apoE-/- mice model was established in vivo.
The primary human umbilical vein endothelial cells (HUVECs) were cultured and the models of vascular endothelial function damaged by H202 were also established in vitro. The following experiments were carried out: (1) the culture and identification of HUVECs; (2) the effect of real-time fluorescence quantitative RT-qPCR and Western blot on the level of eNOS mRNA and protein expression of endothelial cells, and the activation degree of eNOS. (2) (2) the effect of PB on the expression level of eNOS in endothelial cells and whether PB protects endothelial cell function by affecting the expression of eNOS; (3) immunofluorescence microscope observation and fluorescence quantitative detection of NO production in H2O2 induced oxidative damage, and the effect of PB on NO, and to explore whether PB can activate eNOS -NO production pathway can protect endothelial mediated diastolic function.
Result
1.H2O2 can induce oxidative damage in a certain concentration and time of action and selectively inhibit endothelium dependent vasodilatation induced by ACh in the isolated thoracic aorta ring of the rat, which has no obvious effect on the vasoconstrictor function. High concentration or long time H2O2 can cause irreversible loss of vasoconstriction and diastolic function.
2. under the oxidative stress induced by H2O2, PB (5-20 M) protects ACh induced endothelium-dependent vasodilation function in isolated rat thoracic aorta rings.
3.PB inhibited endothelial function induced by H2O2 induced decrease of eNOS activity in isolated vascular rings, but had no significant effect on contractile function.
4. in tissue culture, PB also has protective effects on endothelium-dependent vasodilation of thoracic aorta rings in rats.
5. in the apoE-/- atherosclerosis mouse model, PB can protect the endothelium-dependent vasodilatation function of mice, and this effect has nothing to do with the lipid-lowering effect.
6.PB can increase the p-eNOS/eNOS ratio in human umbilical vein endothelial cells, promote the phosphorylation of eNOS (Ser-1177), activate eNOS oxidation activity, H2O2 to inhibit the expression level of eNOS total protein, PB protects the phosphorylation level of eNOS under the condition of H2O2 induced oxidative damage.
7.PB promotes the production of NO activated by eNOS in human umbilical vein endothelial cells.
conclusion
PB has a protective effect on H2O2 induced endothelium-dependent diastolic dysfunction. The mechanism may be that PB promotes the production of NO by promoting the phosphorylation of eNOS, activating the activity of eNOS oxidase, and thus promoting the formation of NO.
The second part of probucol on the phenotype of smooth muscle cells and its relationship with smooth muscle cell proliferation and migration
background
Vascular smooth muscle cell VSMCs is an important component of vascular wall. The abnormal function of vascular smooth muscle cells is closely related to cardiovascular disease..VSMCs proliferation and synthesis are involved in the formation of atherosclerotic plaques. Smooth muscle cell derived foam cells are one of the cellular components of plaque. Two phenotypes are formed, and pathological changes are associated with synthesis / proliferation. The new view is that the stem cells around the vessel or blood source are the main source of the plaque formation. They have some SMC phenotypic markers, but they are different from the function of ordinary smooth muscle cells and have more characteristics of stem cells. Therefore, this multipotent stem is proposed. Cellular smooth muscle cells are the basis of SMC's involvement in vascular pathological changes. Therefore, the increase of SMC stem cell activity is related to the proliferation or synthesis of SMC in vascular lesions, mainly with the decrease of contractile proteins of highly differentiated smooth muscle cells (including alpha -actin, SM22, calponin and SM-MHC (SM1, SM2)) and the rise of stem cell markers.
Animal experiments have found that probucol can inhibit vascular restenosis after balloon dilatation of rabbit aorta, inhibit the proliferation and migration of smooth muscle cells, inhibit intima thickening, narrowing of the lumen, and improve vascular remodeling. Therefore, we discuss the protective effect of PB on cardiovascular disease from the mechanism and phenotypic changes of SMC to vascular disease. Whether it is related to SMC phenotype and its effect on SMC proliferation and migration.
objective
To explore the effect of probucol on the proliferation and migration of smooth muscle cells and whether it is related to the phenotypic changes of smooth muscle cells.
Method
(1) the vascular smooth muscle cells of the primary rat were extracted and cultured with tissue block wall method, and the primary VSMCs. was detected by immunofluorescence staining to observe the cell morphology and proliferation and differentiation process during the extraction and culture of the primary cells. PB was used to intervene the vascular tissue in order to observe the migration of the cells from the group in situ; and the cells were inoculated in the cells. The effect of direct counting of PB on cell proliferation was studied.
(2) using Transwell cell migration assay to detect the effects of PB and oxLDL on VSMCs migration.
(3) RT-qPCR technology and Western-blot technique were used to study the phenotypic related protein alpha -actin in VSMCs, the expression of Sox-10 in stem cells, and the change of the expression of the transcriptional activator of smooth muscle cells (myocardin).
Results (1) alpha -actin+SM22+Sox-10- is a phenotypic characteristic of highly differentiated VSMCs.
(2) PB alone inhibits the expression of VSMCs stem cell marker Sox-10 and inhibits myocardin, SM22 expression, but does not affect the expression of Sox-10 induced by the expression of contractile protein alpha -actin to induce oxidative stress to promote Sox-10 expression and down regulation of myocardin expression, while PB can partly reverse the change.
(3) PB inhibited the migration of VSMCs from tissues and the migration and proliferation rate in vitro.
conclusion
In vitro studies showed that PB could inhibit the migration and proliferation of VSMCs in rats. The mechanism may be related to the inhibition of PB on the differentiation and motor ability of smooth muscle stem cells.

【學(xué)位授予單位】：中南大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R96

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