槲皮素对野百合碱诱导的大鼠肺动脉高压的影响

目的:观察槲皮素对野百合碱(MCT)诱导的肺动脉高压大鼠的治疗效果。方法:30只成年雄性SD大鼠随机分成3组:MCT诱导的肺动脉高压组(MCT组)、治疗组和对照组。MCT组和治疗组一次性皮下注射MCT 50mg/kg,饲养21d;对照组一次性皮下注射等量0.9%氯化钠溶液,饲养21d。造模后治疗组以槲皮素100mg.kg-1.d-1灌胃20d;MCT组和对照组以0.9%氯化钠溶液2ml/d灌胃20d。20d后,测定3组大鼠平均肺动脉压(mPAP),计算右心室肥大指数(RVHI);光镜下观察大鼠肺组织形态学的改变及肺血管增殖细胞核抗原(PCNA)增殖度的变化,并计算肺中、小动脉管壁厚度占血管外径的百分比(WT%)和肺动脉管壁面积/管总面积的百分比(WA%)。结果:MCT组的mPAP、RVHI、肺中、小动脉WT%、WA%及PCNA增殖度均显著高于对照组及治疗组。结论:槲皮素可降低MCT所致的大鼠肺血管PCNA表达,抑制MCT诱导的肺部炎症、肺血管重建和肺动脉高压形成,对MCT所致的大鼠肺动脉高压具有治疗作用。     

槲皮素对肺动脉高压大鼠肺组织细胞凋亡的影响

目的:观察槲皮素对肺动脉高压肺组织细胞凋亡的影响。方法:将成年雄性SD大鼠30只,随机分为三组:正常对照组(对照组)、野百合碱(MCT)诱导的肺动脉高压组(MCT组)和槲皮素预防组(预防组),每组10只。MCT组及预防组给予野百碱造模,对照组仅以等量0.9%氯化钠液注射,预防组在造模同时每天给予槲皮素100mg/(kg.d)灌胃,21d后测肺动脉压力并计算右心肥大指数,肺组织切片用免疫组化法和免疫印迹法观察大鼠肺组织细胞凋亡(Bcl-2)情况。结果:MCT组大鼠肺动脉平均压力[MCT组(42.13±6.28)vs.对照组(14.57±1.59),P0.05;MCT组(42.13±6.28)vs.预防组(20.32±3.85),P0.05]、右心肥大指数[MCT组(0.593±0.100)vs.对照组(0.241士0.050),P0.05;MCT组(0.593±0.100)vs.预防组(0.290±0.065),P0.05]、肺组织细胞的Bcl-2蛋白相对表达量[MCT组(0.964±0.009)vs.对照组(0.684±0.014),P0.05;MCT组(0.964士0.009)vs.预防组(0.849±0.009),P0.05]显著高于对照组及预防组;同时预防组大鼠肺动脉压力[预防组(20.32士3.85)vs.对照组(14.57±1.59),P0.05]、右心肥大指数[预防组(0.290±0.065)vs.对照组(0.241±0.050),P0.05]、肺组织细胞的Bcl-2蛋白相对表达量[预防组(0.849±0.009)vs.对照组(0.684士0.014),P0.05]高于对照组。结论:槲皮素具有减缓MCT诱导肺动脉高压大鼠肺组织细胞凋亡的作用。     

肺动脉平滑肌细胞:肺动脉高压的关键治疗靶点

肺动脉高压(PAH)是一种进展快、预后欠佳、死亡率高的心血管疾病.研究表明,肺血管重构是PAH发生发展的重要病理基础,而肺动脉平滑肌细胞的增殖和肥大是PAH肺血管重构的主要病理改变.在PAH时,肺血管平滑肌细胞由收缩表型向增殖状态的合成表型转化,主要表现为肺血管平滑肌细胞的增殖和肥大.上述病理改变最终导致肺血管管腔狭窄...     

L—精氨酸对低氧性肺动脉高压大鼠肺动脉平滑肌细胞凋亡？…

目的 探讨Ｌ－精氨酸（Ｌ－Ａｒｇ）对低氧性肺动脉高压大鼠不同节段肺动脉平滑肌细胞凋亡的影响。方法 将Ｗｉｓｔａｒ大鼠（ｎ＝１９）随机分为对照组（ｎ＝７）、低氧组（ｎ＝６）及低氧＋Ｌ－Ａｒｇ组（ｎ＝６）。经右心导管法测定各组大鼠肺动脉压力和右室（ＲＶ）／左室＋室间隔（ＬＶ＋Ｓ）比值,以分光光度法间接测定血浆一氧化氮（ＮＯ）含量,通过ＴＵＮＥＬ法检测各组大鼠肺动脉压力和右室（ＲＶ）／左室＋室间隔（ＬＶ     

川芎嗪对野百合碱诱导大鼠肺动脉高压的影响

目的 探讨川芎嗪对野百合碱诱导的大鼠肺动脉高压的影响.方法 30只Wistar大鼠随机分为对照组、模型组、治疗组,每组10只.测量各组大鼠干预后肺动脉平均压(mPAP)、颈动脉平均压(mCAP),彩色多普勒超声测量肺动脉流速、肺动脉根部内径,HE染色观察肺组织病理形态改变.结果 肺动脉流速:对照组(49.2±3.1) cm/s、肺动脉高压模型组(78.5±3.3)cm/s,川芎嗪治疗组(61.6±4.2) cm/s.各组大鼠肺动脉根部内径:对照组(2.10±0.05)mm,模型组(2.60±0.02) mm,治疗组(2.30±0.03) mm.各组大鼠平均肺动脉压:对照组(15.3±2.2) mmHg,模型组(28.0±2.1) mmHg,治疗组(20.5±3.0) mmHg.各组大鼠平均颈动脉压,对照组(135±7)mmHg,模型组(134±5)mmHg,治疗组(136±8)mmHg.标本HE染色后在显微镜下观察,对照组大鼠肺动脉血管内皮细胞无水肿坏死,肺动脉管壁结构正常.模型组、治疗组大鼠肺小动脉管内皮细胞肿胀、坏死损伤明显,中层平滑肌细胞增生,胶原纤维增多,管腔狭窄明显.治疗组较模型组大鼠肺小动脉中膜平滑肌细胞增生减轻,胶原纤维减少.结论川芎嗪可以有效地抑制野百合碱诱导的肺动脉高压.     

低氧性肺动脉高压与细胞凋亡相关性的研究进展

<正>低氧性肺动脉高压(HPH)是长期缺氧引起的,以渐进性肺血管阻力升高为主要特征,导致右心室肥厚和纤维化,进一步致右心功能不全和不可逆的右心衰竭,甚至全心衰竭,具有较高的病死率。既往研究阐述了HPH的发病关键在于缺氧引起的肺血管收缩及肺血管重塑,可能涉及血管有肺静脉~([1])及肺动脉的中膜平滑肌细胞和外膜成纤维细胞,但不包括肺动脉的内膜内皮细胞~([2])。其中,肺动脉平滑肌细胞增殖是HPH的主要     

内皮祖细胞移植对肺动脉高压大鼠血流动力学及肺血管结构的影响

目的 探讨大鼠内皮祖细胞(EPC)移植对野百合碱(MCT)所致大鼠肺动脉高压(PAH)的血流动力学及肺血管结构的影响.方法 体外培养,鉴定EPCs.用MCT诱发的PAH模型组(n=11)大鼠,由尾静脉注入标记的EPC,移植第21天测定肺血流动力学参数,计算平均肺动脉压(MPAP),右心指数.观察EPCs移植后分化为血管内皮细胞的能力及肺血管结构变化.结果 移植EPC 3周后,荧光显微镜观察部分标记的EPCs分化为血管内皮细胞.与模型组相比,EPC治疗组(n=10)MPAP明显下降[(25.9±0.7)比(29.35±2.2)mmHg,P<0.05],右心指数明显下降(0.43±0.04比0.49±0.05,P<0.05),肺小动脉厚度指数[WT%:(17.7±3.8)%比(29.8±4.3)%]和面积指数[WA%:(54.6±3.9)%比(74.8±4.5)%]明显下降(P均<0.05).结论 同种异体EPC移植可有效降低肺动脉压力,肺动脉血管壁厚度指标和面积指数,改善右心肥厚.作用机制尚需进一步研究.     

764-3对野百合碱性肺动脉高压大鼠肺动脉胶原沉积的影响

目的：观察７６４－３对野百合碱（ＭＣＴ）性肺动脉高压大鼠肺动脉胶原沉积的影响，探讨其可能的作用机制。方法：将雄性Ｗｉｓｔａｒ大鼠随机分为４组即正常组，正常给药组，ＭＣＴ对照组，ＭＣＴ给药组。给药大鼠从第１５天起，皮下注射７６４－３（４０ｍｇ／ｋｇ）１次／日。实验结束时，行血流动力学和病理形态学检查，并测定肺动脉羟脯氨酸（ＨＹＰ）和总蛋白含量。结果：ＭＣＴ性肺动脉高压大鼠肺动脉羟脯氨酸含量较正常组明显增高，平均分别为２４９．５±４９．９μｇ和１２４．２±２１．７μｇ（Ｐ＜０．００１），泡内肺肌型动脉中膜平滑肌细胞（ＳＭＣ）肥大、呈分泌型改变，细胞间胶原沉积；７６４－３能显著降低肺动脉羟脯氨酸含量（平均由２４９．５±４９．９μｇ降至１８６．８±３８．５μｇ，Ｐ＜０．０１），中膜ＳＭＣ结构逆转，胞体多细长，细胞间胶原减少。结论：７６４－３能部分抑制胶原在肺动脉壁的过度沉积，降低ＭＣＴ性肺动脉高压。而其减少胶原沉积、降低肺动脉高压的机制，很可能是通过逆转中膜ＳＭＣ表型改变     

PI3K/Akt/FoxO1信号通路对人源肺动脉平滑肌细胞及肺动脉高压大鼠细胞凋亡的影响

目的 探究磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(Akt)/叉头框蛋白O1(FoxO1)信号通路对人源肺动脉平滑肌细胞(hPASMC)及肺动脉高压大鼠细胞凋亡的影响。方法 细胞实验部分,将hPASMC分为4组：(1)空白对照组;(2)血小板源性生长因子-BB(PDGF-BB)组;(3)PDGF-BB+LY294002组;(4)PDGF-BB+紫杉醇(paclitaxel)组。采用TUNEL检测细胞凋亡,采用蛋白质印迹法检测Bcl-2、裂解的胱天蛋白酶-3(cleaved caspase-3)和PI3K/Akt/FoxO1信号通路相关蛋白表达水平。动物实验部分,将12只SD大鼠随机分为4组：(1)空白对照组;(2)野百合碱(MCT)组;(3)MCT+LY294002组;(4)MCT+paclitaxel组。采用Western blot检测Bcl-2、cleaved caspase-3和PI3K/Akt/FoxO1信号通路相关蛋白表达水平。结果 细胞实验部分：相比于PDGF-BB组,PDGF-BB+LY294002组与PDGF-BB+paclitaxel组的Bcl-2表达水平下降(P&...     

血管重构在动脉型肺动脉高压中的研究进展

动脉型肺动脉高压（PAH）是以肺动脉压力持续升高、肺小动脉结构持续改变为特征的致命性疾病,肺动脉重构是其主要的病理学特点。许多研究发现PAH中血管重构的病理机制主要包括各种细胞的病理学改变和多种分子信号通路的参与,最新的研究指出表观遗传学也参与血管重构,从而导致疾病的发生发展。目前针对PAH发病机制的各种新型药物及新疗法正在被开发,其副作用更小、疗效更佳。本文重点阐述PAH中血管重构的病理机制包括病理学改变、新分子信号通路及表观遗传学内容,以及治疗的新进展。     

Effects and related mechanism of quercetin on thrombin-induced proliferation and migration of rat vascular smooth muscle cells

<正>Objective To investigate the effects and related mechanism of quercetin on thrombin-induced proliferation and migration of rat vascular smooth muscle cells(VSMCs).Methods Third to fifth generation VSMCs were divided into three groups,including control group     

Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling

RATIONALE: Severe pulmonary arterial hypertension (SPH) is a frequently lethal condition characterized by pulmonary vascular remodeling and right heart strain or failure. SPH is also often associated with autoimmune and collagen vascular disorders. OBJECTIVES: To study the effects of T cells on the development of experimental SPH. METHODS: Athymic nude rats lacking T cells were treated with a single subcutaneous injection of vascular endothelial growth factor (VEGF) receptor blocker SU5416 (20 mg/kg) to induce pulmonary vascular endothelial cell apoptosis. Immunohistochemical analysis and IL-4 levels of the lung tissue were performed. Cell death and proliferation were assessed by Western blot and immunohistochemistry. MEASUREMENTS AND MAIN RESULTS: In contrast to SU5416-treated euthymic rats that develop SPH only in combination with chronic hypoxia, athymic nude rats developed SPH and vascular remodeling (similar to clinical SPH) at normoxic conditions as demonstrated by measurements of pulmonary artery pressure and right ventricle hypertrophy. Pulmonary arterioles became occluded with proliferating endothelial cells and were surrounded by mast cells, B cells, and macrophages. IL-4, proliferating cell nuclear antigen, and collagen type I levels were markedly increased in SU5416-treated athymic rat lungs. Antibody deposition was noted along the vascular endothelium in rats with SPH. Finally, protection from SPH was conferred by immune challenge with spleen cells from euthymic nude rats. CONCLUSIONS: These studies demonstrate the importance of a complete, intact immune system in protecting against pulmonary angioproliferation in this new model of SPH as well as the importance of intact VEGF receptor signaling for lung endothelial cell homeostasis.     

Intermedin modulates hypoxic pulmonary vascular remodeling by inhibiting pulmonary artery smooth muscle cell proliferation

BackgroundHypoxic pulmonary arterial hypertension (PAH) is a disabling disease with limited treatment options. Hypoxic pulmonary vascular remodeling is a major cause of hypoxic PAH. Pharmacological agents that can inhibit the remodeling process may have great therapeutic value.ObjectiveTo examine the effect of intermedin (IMD), a new calcitonin gene-related peptide family of peptide, on hypoxic pulmonary vascular remodeling.MethodsRats were exposed to normoxia or hypoxia (∼10% O₂), or exposed to hypoxia and treated with IMD, administered by an implanted mini-osmotic pump (6.5 μg/rat/day), for 4 weeks. The effects of IMD infusion on the development of hypoxic PAH and right ventricle (RV) hypertrophy, on pulmonary vascular remodeling, on pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis, and on the activations of l-arginine nitric oxide (NO) pathway and endoplasmic reticulum stress apoptotic pathway were examined.ResultsRats exposed to hypoxia developed PAH and RV hypertrophy. IMD treatment alleviated PAH and prevented RV hypertrophy. IMD inhibited hypoxic pulmonary vascular remodeling as indicated by reduced wall thickness and increased lumen diameter of pulmonary arterioles, and decreased muscularization of distal pulmonary vasculature in hypoxia-exposed rats. IMD treatment inhibited PASMC proliferation and promoted PASMC apoptosis. IMD treatment increased tissue level of constitutive NO synthase activity and tissue NO content in lungs, and enhanced l-arginine uptake into pulmonary vascular tissues. IMD treatment increased cellular levels of glucose-regulated protein (GRP) 78 and GRP94, two major markers of endoplasmic reticulum (ER) stress, and increased caspase-12 expression, the ER stress-specific caspase, in lungs and cultured PASMCs.ConclusionsThese results demonstrate that IMD treatment attenuates hypoxic pulmonary vascular remodeling, and thereby hypoxic PAH mainly by inhibiting PASMC proliferation. Promotion of PASMC apoptosis may also contribute to the inhibitory effect of IMD. Activations l-arginine–NO pathway and of ER stress-specific apoptosis pathway could be the mechanisms mediating the anti-proliferative and pro-apoptotic effects of IMD.     

PDGFR-β反义寡核苷酸对大鼠血管平滑肌细胞凋亡的影响

目的 :探讨血小板衍化生长因子 β受体 （PDGFR- β）反义寡核苷酸对培养的大鼠血管平滑肌细胞 （VSMC）凋亡的影响。方法 :建立 SD大鼠胸主动脉 VSMC体外增殖模型 ,取 5～ 10代细胞为实验对象 ,按实验目的分为以下几组 :1反义寡核苷酸组 ;2正义寡核苷酸组 ;3错义寡核苷酸 ;4空白对照组。利用透射电镜等观察 VSMC加药前后形态学和超微结构的变化 ,采用原位末端脱氧核苷酸转移酶介导的 d U TP缺口末端标记法 （TU NEL）和流式细胞仪观察和分析 PDGFR- β反义寡核苷酸对 VSMC凋亡的影响。结果 :1加药后 2 4h细胞形态和超微结构较加药前无明显改变 ,48h细胞形态和超微结构较加药前有明显改变。2加药后 2 4h TU NEL 染色各组未发现凋亡细胞 ,48h后反义寡核苷酸组细胞爬片染色有较多凋亡阳性细胞出现。 3加药 2 4h流式细胞仪检测未发现加药组细胞凋亡量与对照组之间有显著差异 ,48h加药组细胞凋亡量明显高于对照组。结论 :PDGFR- β反义寡核苷酸对大鼠VSMC凋亡有诱导作用。     

Circulating smooth muscle progenitor cells in arterial remodeling

The proliferation and migration of vascular smooth muscle cells (SMCs) from the media toward the intimal layer are key components in vascular proliferative diseases. In addition, the differentiation of circulating bone marrow-derived mononuclear cells (BMMCs) into SMCs has been described to contribute to lesion progression in experimental models of atherosclerosis, transplant arteriosclerosis, and neointima formation. In vitro, CD14⁺ BMMCs from peripheral blood acquire a spindle-shaped phenotype and express specific SMC markers in response to platelet-derived growth factor-BB. However, the ‘trans-differentiation’ capacity of BMMCs into definitive SMCs in vivo remains a highly controversial issue. Whereas SMCs within atherosclerotic plaques have been demonstrated to be exclusively of local origin, more severe injury models have shown a wide diversity of SMCs or smooth muscle-like cells derived from BMMCs. In hindsight, these discrepancies may be attributed to methodological differences, e.g., the use of high-resolution microscopy or the specificity of the SMC marker proteins. In fact, the analysis of mouse strains that express marker genes under the control of a highly specific smooth muscle-myosin heavy chain (SM-MHC) promoter and a time-course analysis on the dynamic process of neointima formation have recently shown that BMMCs temporarily express α-smooth muscle actin, not SM-MHC. Additionally, BM-derived cells disappear from the neointimal lesion after the inflammatory response to the injury has subsided. Although CD14⁺/CD68⁺ have important paracrine effects on arterial lesion progression, BMMCs account for more of the ‘SMC-like macrophages’ than the highly ‘trans-differentiated’ and definitive SMCs in vivo. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".