本文關(guān)鍵詞： 肺動脈高壓 泛素-蛋白酶體系統(tǒng) Caspase-3 硼替佐米 大鼠　出處：《山東大學(xué)》2012年碩士論文　論文類型：學(xué)位論文

【摘要】：背景與目的肺動脈高壓(pulmonary arterial hypertension, PAH)是小兒先天性心臟病的常見并發(fā)癥之一,以持續(xù)增高的肺動脈壓并最終導(dǎo)致右心衰為特點的難治性疾病。肺動脈血管內(nèi)皮損傷、平滑肌細胞過度增殖導(dǎo)致的肺血管重構(gòu)是肺動脈高壓形成的基本病理特征。多數(shù)研究認為肺血流增加,血管內(nèi)皮細胞損傷,平滑肌細胞表型改變、過度增殖、凋亡減少,肺血管床重構(gòu)和管腔變窄,導(dǎo)致肺動脈高壓。肺動脈高壓的發(fā)病機制涉及多種復(fù)雜的細胞因子及其調(diào)控網(wǎng)絡(luò),其具體發(fā)病機制尚不清楚。因此,進一步明確肺動脈高壓發(fā)病機制,為肺動脈高壓提供更有效的治療方法具有重要意義。 本研究的目的是觀察在肺動脈高壓發(fā)生發(fā)展過程中泛素蛋白酶體系統(tǒng)的激活情況及硼替佐米對大鼠高血流性肺動脈高壓形成的抑制作用,并探討泛素-蛋白酶體系統(tǒng)及增殖細胞核抗原(PCNA)/Caspase-3在硼替佐米抑制肺動脈高壓形成中可能的作用機制。 方法45只Wistar大鼠隨機分為對照組、分流組、硼替佐米干預(yù)組,每組15只。各組于術(shù)后第8周測量右心室平均收縮壓(RVSP).右心室肥厚指數(shù)(RVHI), HE染色觀察肺小動脈形態(tài)學(xué)改變,計算WT%及WA%。采用免疫組化法、Western Blot法檢測肺組織中Ub、PCNA、Caspase-3的蛋白表達,VWestern Blot法檢測各組大鼠肺組織中NF-κB的活化情況。 結(jié)果與對照組相比,分流組大鼠肺動脈管壁顯著增厚、官腔狹窄,RVSP、RVHI及WT%、WA%增高(P均0.01),Ub、PCNA、Caspase-3蛋白表達增強(P0.05),NF-κB活性增強。與分流組相比,應(yīng)用硼替佐米干預(yù)8周后大鼠肺動脈管壁增厚及管腔狹窄程度明顯減輕,(?)RVSP、RVHI及WT%、WA%降低(P0.01),Ub、PCNA蛋白表達減弱(P0.05), Caspase-3蛋白表達增強(P0.05),NF-κB活性受抑制。 結(jié)論高肺血流性肺動脈高壓可激活體內(nèi)泛素-蛋白酶體系統(tǒng)。硼替佐米可能通過影響NF-κB信號通道來調(diào)節(jié)肺動脈平滑肌中PCNA/Caspase-3表達而起到抑制高肺血流性肺動脈高壓形成的作用。
[Abstract]:Background & objective Pulmonary arterial hypertensionis one of the common complications of congenital heart disease in children. Pulmonary vascular remodeling caused by excessive proliferation of smooth muscle cells is the basic pathological feature of pulmonary hypertension. Pulmonary vascular bed remodeling and narrowing of the lumen lead to pulmonary hypertension. The pathogenesis of pulmonary hypertension involves a variety of complex cytokines and regulatory networks. It is of great significance to clarify the pathogenesis of pulmonary hypertension and to provide more effective treatment for pulmonary hypertension. The aim of this study was to observe the activation of the ubiquitin proteasome system during the development of pulmonary hypertension and the inhibitory effect of bortezomil on the formation of high blood flow pulmonary hypertension in rats. The possible mechanism of ubiquitin proteasome system and proliferating cell nuclear antigen (PCNA) -PCNA / Caspase-3 in the inhibition of pulmonary hypertension by bortezomil was discussed. Methods Forty-five Wistar rats were randomly divided into control group, shunt group and bortezomil intervention group, 15 rats in each group. The mean systolic blood pressure of right ventricle was measured at the 8th week after operation, the right ventricular hypertrophy index was measured and the morphological changes of pulmonary arterioles were observed by HE staining. WT% and WAG were calculated. The expression of Ubhln PCNAfi-Caspase-3 protein in lung tissue was detected by immunohistochemical method and Western Blot method was used to detect the activation of NF- 魏 B in lung tissue of rats in each group. Results compared with the control group, the pulmonary artery wall of shunt group was significantly thickened, and the RVSPN RVHI and WTA increased (P < 0.01) in the shunt group, and the activity of NF- 魏 B was increased in the shunt group compared with the shunt group. The thickness of pulmonary artery wall and the degree of lumen stenosis were significantly reduced after 8 weeks of intervention with bortezomil. The expression of Caspase-3 protein increased and the activity of NF- 魏 B was inhibited. Conclusion High pulmonary flow pulmonary hypertension can activate the ubiquitin proteasome system in vivo. Bortezomil may inhibit the formation of high pulmonary flow pulmonary hypertension by regulating the expression of PCNA/Caspase-3 in pulmonary artery smooth muscle by affecting NF- 魏 B signal channel.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2012
【分類號】：R725.4

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