动脉型肺动脉高压分子标志基因的筛选与鉴定

目的：本研究旨在筛选和鉴定参与动脉型肺动脉高压（pulmonary arterial hypertension,PAH）发病的关键基因及相关信号通路,为进一步的转化医学研究提供新靶点。方法：从美国国立生物技术信息中心的GEO(Gene Expression Omnibus)数据库中获取人GSE113439、GSE117261、GSE48149和GSE53408基因芯片数据集,经过数据筛选后确定PAH组103例和对照组56例进行比较分析。采用NetworkAnalyst软件筛选差异基因（differentially expressed genes,DEGs）,Enrichr和Metascape进行基因本体论（gene ontology,GO）和京都基因和基因组数据库（Kyoto Encyclopedia of Genes and Genomes,KEGG）分析,STRING和Cytoscape建立蛋白质-蛋白质相互作用（protein-protein interaction,PPI）网络确定潜在的枢纽基因。采用野百合碱构建PAH大鼠模型,通过测量血液动力学参数与组织形态学观察造模是否成功...     

己糖激酶Ⅱ与Warburg效应

肿瘤细胞在氧气充足的情况下通过葡萄糖的无氧氧化代谢方式为细胞提供能量的现象称为Warburg效应。己糖激酶是细胞糖酵解中的第一个限速酶,其中己糖激酶-Ⅱ与肿瘤细胞的糖酵解代谢、细胞增殖和凋亡等功能有着更为密切的联系。在肿瘤细胞中,基因水平的改变,信号通路的影响,促使己糖激酶高表达和活性增加,保证了肿瘤细胞糖酵解的快速进行。己糖激酶可通过与线粒体外膜结合促进糖酵解、抑制细胞凋亡和调节细胞自噬影响肿瘤细胞的功能。己糖激酶有望成为肿瘤治疗中的重要靶点。     

结缔组织病相关的肺动脉高压研究进展

肺动脉高压是结缔组织病（CTD）的严重并发症之一。结缔组织病中最常受累的是系统性硬化症（SSc）,而混合性结缔组织病（MCTD）、系统性红斑狼疮（SLE）及炎性肌病包括多肌炎和皮肌炎也常被累及。结缔组织病相关的肺动脉高压引起的原因不仅是肺动脉的病变,慢性血栓的形成,自身免疫反应和肺间质病变也是引起肺动脉高压的原因之一。由于其症状出现晚且不典型,预后甚差,死亡率高,因此对结缔组织病相关的肺动脉高压早期诊断,及时合理的治疗十分重要。     

线粒体分裂在肺动脉高压肺血管重构中的作用

肺动脉高压(pulmonary hypertension,PH)是一类以肺血管阻力进行性升高为主要特征的疾病,其发病率约为每年2. 0～7. 6/100万,患病率则为11～26/100万[1].PH致残、致死率高,预后差,是目前心血管疾病治疗的难点之一[1].目前治疗PH的药物包括L型钙离子通道拮抗剂、磷酸二酯酶抑制剂...     

细胞分裂周期蛋白42通过内皮-间充质转化参与动脉型肺动脉高压小鼠右心室纤维化

目的：探讨细胞分裂周期蛋白42(Cdc42)是否通过内皮-间充质转化（EndMT）参与动脉型肺动脉高压（PAH）小鼠右心纤维化。方法：健康雄性C57BL/6小鼠（5～8周龄）18只,随机分成常氧对照（NC）组、PAH模型[SU5416（血管内皮生长因子受体2抑制剂）+低氧,SuHx]组和SuHx+ML141(Cdc42抑制剂)组,每组6只。所有存活小鼠在4周后用异氟烷麻醉,行心脏超声检查及右心室收缩压（RVSP）监测,之后处死小鼠。用HE和Masson染色观察小鼠右室心肌细胞改变及纤维化程度。使用磁珠分选小鼠心脏内皮细胞并用不同条件处理。通过Western blot检测小鼠心脏组织Cdc42表达水平及内皮细胞Cdc42和EndMT相关蛋白[波形蛋白（vimentin）、α-平滑肌肌动蛋白（α-SMA）、血小板内皮细胞黏附分子1(PECAM-1/CD31)、血管内皮钙黏蛋白（VE-cadherin）和锌指蛋白Snail]表达水平,同时用倒置显微镜观察各组内皮细胞形态。结果：体内实验结果显示,与NC组相比,SuHx组小鼠心脏组织Cdc42表达水平显著升高（P<0.05）;预防给予ML...     

血浆B型利钠肽预测肺动脉高压的价值

目的:探讨血浆B型利钠肽(BNP)浓度预测肺动脉高压的价值。方法:采用化学发光微粒子免疫分析(CMIA)测定48例肺动脉高压患者和46例健康体检正常者外周血浆BNP浓度。超声心动图根据三尖瓣返流估测肺动脉收缩压(SPAP)。比较正常对照组和肺动脉高压组血浆BNP浓度以及统计分析血浆BNP浓度与肺动脉高压之间相关性。结果:正常对照组血浆BNP浓度与肺动脉高压组有显著性差异(P<0.05),轻、中度肺动脉高压组与重度肺动脉高压组血浆BNP浓度无统计学差异(P>0.05),血浆BNP浓度与肺动脉高压有相关性(r=0.394,P<0.01)。结论:血浆BNP浓度与肺动脉高压存在相关性,但血浆BNP浓度并不代表肺动脉高压严重程度。     

低氧性动脉高压大鼠肺动脉壁Ⅰ,Ⅲ型胶原及其mRNA的变化

用双醋酸－－胃蛋白消化法提取可溶性Ⅰ、Ⅲ型胶原混俣物，用β－巯基乙醇阻断－ＳＤＳ－ＰＡＧＥ分出Ⅲ型胶原之单α１（Ⅲ）条带测定常压低氧大鼠肺外肺动脉中Ⅰ、Ⅲ胶原比例的变化。结果表明，吸入低氧气体１周／Ⅲ型胶原比值未见有统计学意义的变化；吸入低氧气体３周、Ⅲ型胶原比值明显升高。崦在吸入低氧气体１周时Ｉ型前胶原ｍＲＮＡ已呈有统计学意义之升高。     

生长因子与肺动脉高压形成

生长因子参与肺动脉高压的形成，本文综述了一些生长因子在肺动脉高压中作用机制。     

内皮祖细胞在肺动脉高压中的研究进展

肺动脉高压(pulmonary hypertension,PH)是指在海平面静息状态下平均肺动脉压(mean pulmonaryarterial pressure,mPAP)≥20 mmHg,肺血管阻力(pulmonaryvascular resistance,PVR)≥3 Wood units 的一种疾病或病理生理综...     

肺动脉高压相关标记物研究进展

近年来,随着对肺动脉高压发病机制的进一步认识,肺动脉高压的诊断和治疗有了很大进步。靶向药物的使用在一定程度上改善了肺动脉高压患者的病情发展,但肺动脉高压的远期预后仍不容乐观。因此,寻找能监测病情严重程度、预后及患者对治疗反应的可靠指标显得至关重要。目前国内外有不少研究致力于寻找非侵入性的、能客观评价病情严重程度及预后的生物标记物。本文针对研究发现的部分标记物作一简要综述。     

The role of platelets in the development and progression of pulmonary arterial hypertension

Pulmonary arterial hypertension is a multifactorial disease characterized by vasoconstriction, vascular remodeling, inflammation and thrombosis. Although an increasing number of research confirmed that pulmonary artery endothelial cells, pulmonary artery smooth muscle cells as well as platelets have a role in the pulmonary arterial hypertension pathogenesis, it is still unclear what integrates these factors. In this paper, we review the evidence that platelets through releasing a large variety of chemokines could actively impact the pulmonary arterial hypertension pathogenesis and development. A recent publication revealed that not only an excess of platelet derived cytokines, but also a deficiency may be associated with pulmonary arterial hypertension development and progression. Hence, a simple platelet blockade may not be a correct action to treat pulmonary arterial hypertension. Our review aims to analyse the interactions between the platelets and different types of cells involved in pulmonary arterial hypertension pathogenesis. This knowledge could help to find novel therapeutic options and improve prognosis in this devastating disease.     

The remodeling of connexin in the hypertrophied right ventricular in pulmonary arterial hypertension and the effect of a dual ET receptor antagonist (bosentan)

Studies on the role of connexins (Cxs) in the pathogenesis of right ventricular (RV) hypertrophy in pulmonary arterial hypertension (PAH) have not been reported to date. Therefore, we established a rat model of PAH induced by monocrotaline (MCT), and they were randomized to three groups: Control, MCT, and MCT+bosentan. Through electromicroscopy, in the control group, the gap junctions were long and frequent in intercalated disks, and short and rare at the sites of side–side cell junctions. In the MCT group, the opposite distribution was detected. In the MCT+bosentan group, the distribution of gap junctions was similar to that in the control group. Using immunoconfocal microscopy, most of the Cx43 staining was aggregated at the cell termini, and staining was weak at the sites of side–side cell junctions in the control group. However, the distribution of Cx43 was opposite in the MCT group. In the MCT+bosentan group, the result was similar to that in the control group. Therefore, perturbation of connexin distribution may be associated with RV hypertrophy. Improving the distribution of Cx43 in RV myocardium may be one of the mechanisms of a dual ET receptor antagonist partly reversing the RV hypertrophy.     

内皮-间充质转化在肺动脉高压发病机制中的研究进展

正肺动脉高压(pulmonary hypertension,PH)是由多种已知和未知原因引起的肺循环血压异常升高的一种病理生理综合症,主要累及心血管及呼吸系统~([1-2])。根据2015年最新PH的临床分型,PH分为动脉型肺动脉高压(pulmonary arterial hypertension,PAH)、左心疾病所致PH、肺部疾病或缺氧所致PH、     

Pyrrolidine dithiocarbamate attenuates the development of monocrotaline-induced pulmonary arterial hypertension

We aimed to demonstrate the potential protective effects of pyrrolidine dithiocarbamate (PDTC) on monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Adult male rats were randomly assigned to 4 groups: control group, MCT-treated rats only, MCT-injected rats treated with PDTC, and PDTC-treated rats only. Blood and tissue samples were collected after the sacrifice. Levels of malondialdehyde (MDA) were measured by using the thiobarbituric acid method. Total antioxidant status (TAS) was determined using a commercially available ImAnOx kit. A histopathological evaluation was accomplished by scoring the degree of severity. Endothelial damage of the main pulmonary artery was evaluated by immunohistochemical labeling of endothelial cells using anti-rat endothelial cell antigen 1 (RECA-1) antibody. MCT-induced right ventricular hypertrophy (RVH) was reduced significantly in the MCT + PDTC-treated group. MDA levels were significantly lowered in the MCT + PDTC-treated group. TAS was significantly higher in the MCT + PDTC-treated group when compared with the rats with PAH. Histopathological examination demonstrated that PDTC treatment reduced the development of inflammation, hemorrhage and congestion, and collagen deposition. In conclusion, PDTC attenuated PAH and protected pulmonary endothelium in rats administered MCT. These findings suggest that PDTC treatment may provide a new effective therapeutic approach in the treatment of PAH.     

RhoA/Rho激酶信号通路与肺动脉高压

目前研究已发现RhoA/Rho激酶信号通路参与了人体多种疾病的形成,如高血压、冠心病、脑率中等.肺动脉高压的病理学改变包括内皮细胞的损伤、增殖,肺血管平滑肌细胞的高反应性,炎症细胞迁移和黏附以及肺小血管形成和栓塞;Rho激酶调节细胞的多种生物学行为和功能,如收缩、黏附、迁移、增殖、凋亡、基因表达等.研究表明RhoA/R...     

4种肺动脉高压动物模型肺血管重构模式的差异研究

目的：探讨4种肺动脉高压（PH）动物模型肺血管重构模式的差异。方法:雄性SD大鼠（350-400g），分别通过腹主动脉-腔静脉分流（A-VF, n=10）、左肺切除（PE, n=10）、野百合碱注射（MCT, n=10）、左肺切除+MCT（PE+MCT,n=12）4种方法建立PH模型。检测平均肺动脉压力(mPAP）、RV/(LV+S)重量比值、肺小动脉中膜厚度百分比（WT%）、无肌性动脉肌化程度和新生内膜(neointima)形成、新生内膜增殖度和血管阻塞计分（VOS）。结果:在PE+MCT组（肺切除术后5周，MCT注射后4周）右肺腺泡内血管出现了新生内膜病变，其它组均没有新生内膜病变形成。PE+MCT组的动物出现了严重的右心室肥大，动脉中膜明显增厚，平均肺动脉压（mPAP）和无肌性血管肌化程度显著增加；A-VF、PE和MCT组仅形成轻-中度的右心室肥大、mPAP升高和小动脉肌化。结论:左肺切除联合应用MCT能成功诱导大鼠PH新生内膜模型，该模型能更好地模拟人类严重PH的病理改变，是研究梗阻性PH更为适用的动物模型。     

Cerium oxide nanoparticles attenuate monocrotaline induced right ventricular hypertrophy following pulmonary arterial hypertension

Cerium oxide (CeO₂) nanoparticles have been posited to exhibit potent anti-oxidant activity which may allow for the use of these materials in biomedical applications. Herein, we investigate whether CeO₂ nanoparticle administration can diminish right ventricular (RV) hypertrophy following four weeks of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Male Sprague Dawley rats were randomly divided into three groups: control, MCT only (60 mg/kg), or MCT + CeO₂ nanoparticle treatment (60 mg/kg; 0.1 mg/kg). Compared to the control group, the RV weight to body weight ratio was 45% and 22% higher in the MCT and MCT + CeO₂ groups, respectively (p < 0.05). Doppler echocardiography demonstrated that CeO₂ nanoparticle treatment attenuated monocrotaline-induced changes in pulmonary flow and RV wall thickness. Paralleling these changes in cardiac function, CeO₂ nanoparticle treatment also diminished MCT-induced increases in right ventricular (RV) cardiomyocyte cross sectional area, β-myosin heavy chain, fibronectin expression, protein nitrosylation, protein carbonylation and cardiac superoxide levels. These changes with treatment were accompanied by a decrease in the ratio of Bax/Bcl2, diminished caspase-3 activation and reduction in serum inflammatory markers. Taken together, these data suggest that CeO₂ nanoparticle administration may attenuate the hypertrophic response of the heart following PAH.     

Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases

Pulmonary arterial hypertension is a severe complication of connective tissue diseases. It is currently well established that pulmonary arterial hypertension associated with connective tissue diseases such as systemic sclerosis is frequently less responsive or even refractory to pulmonary vasodilator therapies. In that setting, pulmonary venoocclusive disease is believed to contribute to treatment failures. We therefore hypothesized that pulmonary arterial hypertension associated with connective tissue diseases may be associated with obstructive lesions of pulmonary veins. Lung samples from 8 patients with pulmonary arterial hypertension associated with connective tissue disease (4 limited systemic sclerosis, 2 systemic lupus erythematosus, 1 mixed connective tissue diseases, and 1 rheumatoid arthritis) were studied by light microscopy and analyzed by immunohistochemistry (5 postmortem samples, 3 explants after lung transplantation). Findings were compared with 29 pulmonary arterial hypertension cases from patients displaying neither connective tissue diseases nor associated conditions. We found that (a) 6 (75%) of 8 patients with pulmonary arterial hypertension associated with connective tissue diseases showed significant obstructive pulmonary vascular lesions predominating in veins/preseptal venules, as compared with 5 (17.2%) of 29 non-connective tissue diseases control pulmonary arterial hypertension; (b) lesions of small muscular arteries were consistently present in pulmonary arterial hypertension associated with connective tissue diseases, showing mostly intimal fibrosis and thrombotic lesions; and (c) 6 of 8 lung samples from patients with pulmonary arterial hypertension associated with connective tissue diseases revealed perivascular inflammatory infiltration. In conclusion, our study highlights the fact that pulmonary arterial hypertension complicating the course of connective tissue diseases may be characterized by a more frequent involvement of pulmonary veins and may thus explain why these patients are less prone to respond to specific pulmonary arterial hypertension treatment as compared with idiopathic pulmonary arterial hypertension.