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1.
目的:观察低氧性肺动脉高压小鼠体内脂质代谢的变化,探讨脂质代谢异常在低氧性肺动脉高压发生发展中的意义。方法:SPF级雄性C57BL/6小鼠20只,随机分为2组(n=10):常氧组和低氧组。常压连续低氧3周(9%~11% O2,23 h/d)复制慢性低氧性肺动脉高压模型,测定小鼠右心室压(RVSP)和右心室与左心室加室间隔重量比,Elisa法检测血浆中总胆固醇(TC)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)的含量;real-time PCR法检测肝组织中3-羟基-3-甲基戊二酸单酰辅酶A还原酶(HMGCR)、低密度脂蛋白受体(LDLR)、清道夫受体B1(SR-B1)、固醇调节元件结合因子2(SREBF2)等基因的表达。结果:低氧组小鼠RVSP、RV/(LV+S)显著高于常氧组(P<0.05),血浆中HDL含量及HDL/LDL比值较常氧组显著降低(P<0.05),肝组织中LDLR、SR-B1基因表达较常氧组显著下调(P<0.05);RVSP与HDL/LDL比值及LDLR、SR-B1基因表达呈显著负相关(P<0.05)。结论:脂质代谢异常参与小鼠低氧性肺动脉高压的形成。  相似文献   

2.
目的:探讨外源性apelin对小鼠慢性低氧性肺动脉高压的作用及其机制。方法:SPF级雄性apoE基因敲除(apoE-KO)小鼠30只,随机均分为3组(n=10),即常氧组、低氧组和低氧+apelin组,apelin组小鼠每天于低氧前经腹腔注射apelin-13(10 nmol/(kg·d)),其他组腹腔注射相同体积的生理盐水。采用常压连续低氧方法(9%~11% O2,23 h/d)复制慢性低氧性肺动脉高压模型。低氧3周后,采用右心导管法测定小鼠右心室压(RVSP)和右心室与左心室加室间隔重量比,Elisa法检测血浆中高密度脂蛋白(HDL)、低密度脂蛋白(LDL)和总胆固醇(TC)的含量;real-time PCR法检测肝组织中三磷酸腺苷结合盒转运体A1(ABCA1)、清道夫受体B1(SR-B1)、低密度脂蛋白受体(LDLR)和3-羟基-3-甲基戊二酸单酰辅酶A还原酶(HMGCR)等基因的表达。Western blot法检测小鼠肺组织中过氧化物酶体增殖物激活受体γ(PPARγ)蛋白的表达。结果:①低氧组小鼠RVSP、RV/(LV+S)较常氧组分别高87%、85%(P均<0.05),apelin组小鼠RVSP、RV/(LV+S)较低氧组分别低39%、33%(P均<0.05)。②apelin组小鼠血浆中HDL-C含量、HDL/LDL比值分别较hypoxia组高21%、20%(P均<0.05),而血浆中TC、LDL-C含量两组间无显著差异(P均>0.05)。③apelin组小鼠肝组织中LDLR、SR-B1、ABCA1基因表达分别较低氧组上调241%、112%、69%(P均<0.05),而HMGCR基因表达下调45%(P<0.05)。④apelin组小鼠肺组织中PPARγ蛋白表达较低氧组上调47%。结论:Apelin可降低小鼠低氧性肺动脉高压,其机制与调节脂质代谢有关。  相似文献   

3.
目的:观察低氧性肺动脉高压小鼠肺组织中载脂蛋白E(apoE)蛋白表达的变化,以探讨低氧性肺动脉高压形成过程中apoE蛋白表达的变化及可能的意义。方法:SPF级雄性野生型(WT)C57BL/6小鼠和雄性apoE基因敲除(apoE-KO)小鼠各20只,各随机再分为2组(n=10):常氧组和低氧组,共4组。常压连续低氧3周(9%~11% O2,23 h/d)复制慢性低氧性肺动脉高压模型,采用右心导管法测定小鼠右心室压(RVSP),计算右心室与左心室加室间隔重量比RV/(LV+S),ELISA法检测血浆中高密度脂蛋白(HDL)、低密度脂蛋白(LDL)和总胆固醇(TC)的含量;Western blot法检测肺组织中apoE和过氧化物酶体增殖物激活受体γ(PPARγ)蛋白的表达。结果:①低氧组WT小鼠RVSP、RV/(LV+S)分别较常氧组高68%和59%(P均<0.05),血浆中HDL含量及HDL/LDL比值分别较常氧组低17%和40%(P均<0.05),同时肺、肝组织中apoE及肺组织中PPARγ的蛋白表达分别较常氧组下调48%、52%和37%(P均<0.05),RVSP与apoE及PPARγ蛋白表达均呈显著负相关(P均<0.01);②低氧组apoE-KO小鼠RVSP、RV/(LV+S)较常氧组分别高96%和86%(P均<0.05),低氧组apoE-KO小鼠RVSP和RV/(LV+S)较低氧组WT小鼠分别高29%和24%(P均<0.05)。结论:小鼠低氧性肺动脉高压的形成与肺组织中apoE蛋白表达下调有关。  相似文献   

4.
目的探索脂肪干细胞(ADSC)移植治疗野百合碱(MCT)诱导的肺动脉高压(PAH)大鼠的适宜细胞数和干预时间。 方法(1)MCT的建模时效和量效:雄性SD大鼠48只分为正常对照组,20 mg/kg、30 mg/kg、40 mg/kg MCT组分别予腹腔注射生理盐水、MCT 20 mg/kg、30 mg/kg、40 mg/kg,4和8周后,右心室插管法检测平均肺动脉压(mPAP),称重法计算右心室肥厚指数(RVHI)。(2)ADSC的治疗量效作用:雄性SD大鼠分别予腹腔注射MCT(30只)和生理盐水(30只),1周后通过颈静脉注射分别移植0.5×106、1.0×106、3.0×106、5.0×106ADSC,其他组予等量生理盐水。移植3周后检测mPAP和RVHI。(3)ADSC的治疗时效作用:雄性SD大鼠30只,分别注射40 mg/kg MCT(24只)和生理盐水(6只)。MCT腹腔注射1 d,1、2周后分别移植1.0×106个ADSC。MCT注射4周后检测mPAP和RVHI。多组间比较采用单因素或双因素方差分析,两两比较采用LSD检验。 结果(1)腹腔注射4周后,30 mg/ kg或40 mg/kg MCT组mPAP和RVHI均升高[mPAP值(24.89±3.31)mmHg,(27.19±2.11)mmHg比(15.80±0.42)mmHg,差异有统计学意义(P均< 0.05);RVHI值0.42±0.06,0.47±0.04比0.25±0.02,差异有统计学意义(P均< 0.05)]。8周后,20 mg/kg或30 mg/ kg MCT组mPAP和RVHI均恢复正常,而40 mg/kg MCT组大鼠全部死亡。(2)40 mg/ kg MCT诱导的PAH大鼠mPAP和RVHI均升高。移植1.0×106个ADSC可降低PAH大鼠的mPAP[(17.24±0.66)mmHg比(27.19±1.73)mmHg,P < 0.05]。移植0.5×106、3.0×106、5.0× 106个ADSC不能降低PAH大鼠的mPAP和RVHI。(3)MCT腹腔注射1周和2周后,移植1.0×106个ADSC可降低PAH大鼠的mPAP。 结论40 mg/kg MCT造模4周可建立稳定的PAH大鼠模型;造模1或2周后移植1.0×106个ADSC能有效降低PAH大鼠的mPAP。  相似文献   

5.
Abstract

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) and suppressed apoptosis. Platelet-derived growth factor (PDGF) is a potent mitogen involved in cell proliferation and migration. PDGF-BB induces the proliferation and migration of PASMCs and has been proposed to be a key mediator in the progression of PAH. Previous studies have shown that PDGF and its receptor are substantially elevated in lung tissues and PASMCs isolated from patients and animals with PAH, but the underlying mechanisms are still poorly manifested. MAP kinases, including extracellular signal-regulated kinase1/2 (ERK1/2), c-Jun NH2-terminal kinase1/2 (JNK1/2), and p38 are the key intracellular signals for stimuli-induced cell proliferation, survival, and apoptosis. Therefore, the purpose of this study is to determine whether PDGF-BB on cell proliferation process is mediated through the MAP kinases pathway in human PASMCs (HPASMCs). Our results showed PDGF-BB-induced proliferating cell nuclear antigen (PCNA), Cyclin A and Cyclin E expression in a concentration-dependent manner. The expression levels of phosphorylated JNK (p-JNK) was upregulated with 20?ng/ml PDGF-BB treatment, while PDGF-BB could not increase phosphorylated ERK1/2 (p-ERK1/2) and p-38 (p-p38) expression. The effects of PDGF-BB on cell proliferation and survival were weakened after the administration of antagonist of the JNK pathway or si-JNK. In addition, PDGF-BB protected against the loss of mitochondrial membrane potentials evoked by serum deprivation (SD) in a JNK-dependent manner. These results suggest that PDGF-BB promotes HPASMCs proliferation and survival, which is likely to be mediated via the JNK pathway.  相似文献   

6.
肺动脉高压(PAH)是一种以血管收缩和重构所致的肺血管阻力升高为病理生理学特征的临床综合征,其呈进行性发展,最终可 导致右心衰竭甚至死亡,预后差。随着对 PAH 病理生理学机制的深入研究,该病所涉不同信号通路的关键位点逐渐被认识,相应的靶向 药物也不断涌现,它们的应用明显改善了PAH患者的生活质量和预后。综述针对PAH 发生发展过程中所涉的3条主要通路:前列环素通路、 内皮素通路和一氧化氮-鸟苷酸环化酶-环磷酸鸟苷通路以及其他靶点(如酪氨酸激酶受体和 Rho 激酶等)而开发的靶向药物研究进展。  相似文献   

7.
Background. In patients with pulmonary hypertension, it is unknown whether the treatment effect of bosentan is dependent on the duration of pulmonary vessel changes. Therefore, we studied the response to bosentan in patients with life-long pulmonary vessel changes (pulmonary arterial hypertension (PAH) due to congenital heart disease (CHD)) and in patients with subacutely induced pulmonary vessel changes (chronic thromboembolic pulmonary hypertension (CTEPH)). Methods. In this open-label study, 18 patients with PAH due to CHD and 16 patients with CTEPH were treated with bosentan for at least one year. All patients were evaluated at baseline and during follow-up by means of the six-minute walk distance (6-MWD) and laboratory tests. Results. Improvement of 6-MWD was comparable in patients with PAH due to CHD (444±112 m to 471±100 m, p=0.02), and in CTEPH (376±152 m to 423±141 m, p=0.03) after three months of treatment. After this improvement, 6-MWD stabilised in both groups. Conclusion. Although duration of pulmonary vessel changes is strikingly different in patients with PAH due to CHD and CTEPH, the effect of one year of bosentan treatment was comparable. The main treatment effect appears to be disease stabilisation and decreasing the rate of deterioration. (Neth Heart J 2009;17:334–8.)  相似文献   

8.
Apelin对大鼠离体肺动脉环的舒张作用及与一氧化氮的关系   总被引:1,自引:0,他引:1  
目的:探讨新的小分子活性肽Apelin对大鼠离体肺动脉环的舒张作用及与一氧化氮(NO)途径的关系,并比较低氧大鼠的肺动脉环对Apelin的舒张反应与正常大鼠的差异。方法:36只大鼠随机分为正常组与低氧组;采用离体血管环灌流法,检测Apelin对去甲肾上腺素(NE)预收缩的大鼠离体肺主动脉环的舒张效应,观察去内皮或用一氧化氮合酶抑制剂(L-NAME)、可溶性鸟苷酸环化酶(sGC)抑制剂(ODQ)孵育后该舒张率的变化。结果:①在正常组大鼠肺动脉环,Apelin(0.01~100 nmol/L)具有浓度依赖性的舒张效应。去除内皮后,Apelin对NE预先收缩的肺血管舒张效应明显减弱(P〈0.01)。L-NAME或ODQ预孵育后,Apelin的舒张效应均明显减弱(P均〈0.01)。②低氧组大鼠的肺动脉环对Apelin的舒张反应明显低于正常组大鼠,在最大浓度100 nmol/L时,Apelin的效应低60.45%(P〈0.01),而两组EC50相比差异无显著性(P〉0.05)。结论:Apelin具有内皮依赖性的舒张肺动脉环的作用,该效应与NO-sGC-cGMP信号途径有关;低氧大鼠的离体肺动脉环对Apelin的舒张反应减弱。  相似文献   

9.
    

Background

A low resting heart rate (HR) is prognostically favourable in healthy individuals and in patients with left heart disease. In this study we investigated the impact of HR at diagnosis on long-term outcome in patients with differently classified precapillary pulmonary hypertension (pPH).

Methods

pPH patients diagnosed as pulmonary arterial (PAH) or inoperable chronic thromboembolic pulmonary hypertension (CTEPH) were registered and regularly followed at our centre Baseline characteristics and events defined as either death or lung transplantation were noted. The prognostic value of HR was analysed using Kaplan Meier estimates, live tables and Cox regression.

Results

206 patients with PAH (148) and inoperable CTEPH (58) were included. The median HR was 82 bpm. pPH with a HR below 82 bpm had a significantly longer overall event-free survival (2409 vs.1332 days, p = .000). This advantage was similarly found if PAH and CTEPH were analysed separately. Although a lower HR was associated with a better hemodynamic and functional class, HR was a strong and independent prognostic marker for transplant free survival even if corrected for age, sex, hemodynamics and functional status.

Conclusion

We show that resting HR at diagnosis is a strong and independent long-term prognostic marker in PAH and CTEPH. Whether reducing HR by pharmacological agents would improve outcome in pPH has to be assessed by future trials with high attention to safety.  相似文献   

10.
    
Pulmonary arterial hypertension (PAH) is characterized by muscularized pulmonary blood vessels, leading to right heart hypertrophy and cardiac failure. However, state-of-the-art therapeutics fail to target the ongoing remodeling process. Here, this study shows that matrix metalloproteinases (MMP)-1 and MMP-10 levels are increased in the medial layer of vessel wall, serum, and M1-polarized macrophages from patients with PAH and the lungs of monocrotaline- and hypoxia-induced PAH rodent models. MMP-10 regulates the malignant phenotype of pulmonary artery smooth muscle cells (PASMCs). The overexpression of active MMP-10 promotes PASMC proliferation and migration via upregulation of cyclin D1 and proliferating cell nuclear antigen, suggesting that MMP-10 produced by infiltrating macrophages contributes to vascular remodeling. Furthermore, inhibition of STAT1 inhibits hypoxia-induced MMP-10 but not MMP-1 expression in M1-polarized macrophages from patients with PAH. In conclusion, circulating MMP-10 could be used as a potential targeted therapy for PAH.  相似文献   

11.
12.
We previously showed that a single nucleotide polymorphism in S100A4 was associated with portopulmonary hypertension (PPHTN) in patients with advanced liver disease. We aimed to determine the association between plasma levels of S100A4 and PPHTN. We performed a case–control study of patients with advanced liver disease. Cases with PPHTN had mean pulmonary artery pressure >25?mmHg, pulmonary vascular resistance >240 dynes s?cm?5 and pulmonary capillary wedge pressure 15?mmHg. Controls with liver disease had right ventricular systolic pressure <40?mmHg and normal right atrial and ventricular morphology by echocardiography. Plasma samples were assayed for S100A4. The study sample included 14 cases with PPHTN and 32 controls with liver disease. There was no difference in mean age between cases and controls (p = 0.52). Seventy-nine percent of cases were female compared with 44% of controls (p?=?0.03). There was no difference in S100A4 levels between cases and controls (p?=?0.58). Both groups had significantly higher S100A4 levels than healthy volunteers (p?<0.05). There was no significant difference in plasma levels of S100A4 between PPHTN patients and controls with liver disease, although liver disease itself was associated with increased S100A4 levels.  相似文献   

13.
14.
    
Recent evidence suggests that glia maturation factor β (GMFβ) is important in the pathogenesis of pulmonary arterial hpertension (PAH), but the underlying mechanism is unknown. To clarify whether GMFβ can be involved in pulmonary vascular remodeling and to explore the role of the IL-6-STAT3 pathway in this process, the expression of GMFβ in PAH rats is examined and the expression of downstream molecules including periostin (POSTN) and interleukin-6 (IL-6) is measured using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The location and expression of POSTN is also tested in PAH rats using immunofluorescence. It is proved that GMFβ is upregulated in the lungs of PAH rats. Knockout GMFβ alleviated the MCT-PAH by reducing right ventricular systolic pressure (RVSP), mean pulmonary arterial pressure (mPAP), and pulmonary vascular remodeling. Moreover, the inflammation of the pulmonary vasculature is ameliorated in PAH rats with GMFβ absent. In addition, the IL-6-STAT3 signaling pathway is activated in PAH; knockout GMFβ reduced POSTN and IL-6 production by inhibiting the IL-6-STAT3 signaling pathway. Taken together, these findings suggest that knockout GMFβ ameliorates PAH in rats by inhibiting the IL-6-STAT3 signaling pathway.  相似文献   

15.
    
Pulmonary arterial hypertension (PAH) comprises a heterogeneous group of diseases with diverse aetiologies. It is characterized by increased pulmonary arterial pressure and right ventricular (RV) failure without specific drugs for treatment. Emerging evidence suggests that inflammation and autoimmune disorders are common features across all PAH phenotypes. This provides a novel idea to explore the characteristics of immunological disorders in PAH and identify immune-related genes or biomarkers for specific anti-remodelling regimens. In this study, we integrated three gene expression profiles and performed Gene Ontology (GO) and KEGG pathway analysis. CIBERSORT was utilized to estimate the abundance of tissue-infiltrating immune cells in PAH. The PPI network and machine learning were constructed to identify immune-related hub genes and then evaluate the relationship between hub genes and differential immune cells using ImmucellAI. Additionally, we implemented molecular docking to screen potential small-molecule compounds based on the obtained genes. Our findings demonstrated the density and distribution of infiltrating CD4 T cells in PAH and identified four immune-related genes (ROCK2, ATHL1, HSP90AA1 and ACTR2) as potential targets. We also listed 20 promising molecules, including TDI01953, pemetrexed acid and radotinib, for PAH treatment. These results provide a promising avenue for further research into immunological disorders in PAH and potential novel therapeutic targets.  相似文献   

16.
Peroxisome proliferator activated receptor alpha (PPARα) agonists are anti-hyperlipidemic drugs that influence fatty acid combustion, phospholipid biosynthesis and lipoprotein metabolism. To evaluate impacts on other aspects of lipid metabolism, we applied targeted metabolomics to liver, heart, brain and white adipose tissue samples from male Swiss-Webster mice exposed to a 5 day, 500 mg/kg/day regimen of i.p. clofibrate. Tissue concentrations of free fatty acids and the fatty acid content of sphingomyelin, cardiolipin, cholesterol esters, triglycerides and phospholipids were quantified. Responses were tissue-specific, with changes observed in the liver > heart >> brain > adipose. These results indicate that liver saturated fatty acid-rich triglycerides feeds clofibrate-induced monounsaturated fatty acid (MUFA) synthesis, which were incorporated into hepatic phospholipids and sphingomyelin. In addition, selective enrichment of docosahexeneoic acid in the phosphatidylserine of liver (1.7-fold), heart (1.6-fold) and brain (1.5-fold) suggests a clofibrate-dependent systemic activation of phosphatidylserine synthetase 2. Furthermore, the observed ∼20% decline in cardiac sphingomyelin is consistent with activation of a sphingomeylinase with a substrate preference for polyunsaturate-containing sphingomyelin. Finally, perturbations in the liver, brain, and adipose cholesterol esters were observed, with clofibrate exposure elevating brain cholesterol arachidonyl-esters ∼20-fold. Thus, while supporting previous findings, this study has identified novel impacts of PPARα agonist exposure on lipid metabolism that should be further explored. Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Supplementary data include an excel file with quantitative values (nmol/g tissue) of all lipids measured in this study (Table S1–5) as well as a table with the scientific name, molecular name and common name of all fatty acids reported (Table S5).  相似文献   

17.
目的:探讨苹果多酚抑制肺动脉高压大鼠肺动脉血管重构的作用及其机制。方法:雄性SD大鼠随机分为对照组(Con),野百合碱(MCT)组,苹果多酚(APP)组,野百合碱+苹果多酚(MCT+APP)组,每组9只。Con组:每天皮下注射1ml生理盐水;APP组:隔天按20mg/kg的剂量腹腔注射苹果多酚;MCT组:按60mg/kg剂量一次性皮下注射MCT;MCT+APP组:一次性皮下注射60mg/kg剂量MCT,隔天按20mg/kg剂量腹腔注射APP,所有处理持续3周。建模完成后,检测各组大鼠平均肺动脉压(mPAP),肺血管阻力(PVR),右心室肥厚指数(RVHI),肺动脉血管环外周长比值(WT%),肺小血管管壁面积和管总面积比值(WA%)。检测肺组织中的白细胞介素1(IL-1),白细胞介素6(IL-6),肿瘤坏死因子α(TNF-α),环氧化酶2(COX-2),髓过氧化物酶(MPO)等炎症通路相关指标,及肺动脉平滑肌细胞内Ca2+和内皮细胞eNOS,NO含量。结果:MCT组大鼠与对照组比较,在动物水平的指标mPAP、PVR、RVHI、WA%、WT%和肺动脉组织内IL-1,IL-6,TNF-α,COX-2,MPO表达量以及肺动脉平滑肌细胞内的Ca2+浓度明显升高(P<0.05),而内皮细胞中的eNOS,NO含量明显下降(P<0.05);苹果多酚治疗组与MCT组大鼠相比上述情况得到改善,其中COX-2和Ca2+指标明显下降,且具有统计学意义(P<0.05)。结论:苹果多酚可通过抑制MCT引起的肺组织内IL-1,IL-6,TNF-α,COX-2升高和肺动脉平滑肌细胞内Ca2+升高以及内皮细胞中eNOS,NO降低,抑制平滑肌细胞增殖,逆转肺血管重构,缓解肺动脉高压。  相似文献   

18.
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by the vascular remodeling of the pulmonary arterioles, including formation of plexiform and concentric lesions comprised of proliferative vascular cells. Clinically, PAH leads to increased pulmonary arterial pressure and subsequent right ventricular failure. Existing therapies have improved the outcome but mortality still remains exceedingly high. There is emerging evidence that the seven-transmembrane G-protein coupled receptor APJ and its cognate endogenous ligand apelin are important in the maintenance of pulmonary vascular homeostasis through the targeting of critical mediators, such as Krűppel-like factor 2 (KLF2), endothelial nitric oxide synthase (eNOS), and microRNAs (miRNAs). Disruption of this pathway plays a major part in the pathogenesis of PAH. Given its role in the maintenance of pulmonary vascular homeostasis, the apelin-APJ pathway is a potential target for PAH therapy. This review highlights the current state in the understanding of the apelin-APJ axis related to PAH and discusses the therapeutic potential of this signaling pathway as a novel paradigm of PAH therapy.  相似文献   

19.
    
Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance and obliterative pulmonary vascular remodelling (PVR). The imbalance between the proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMCs) is an important cause of PVR leading to PAH. Mitochondria play a key role in the production of hypoxia-induced pulmonary hypertension (HPH). However, there are still many issues worth studying in depth. In this study, we demonstrated that NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 like 2 (NDUFA4L2) was a proliferation factor and increased in vivo and in vitro through various molecular biology experiments. HIF-1α was an upstream target of NDUFA4L2. The plasma levels of 4-hydroxynonene (4-HNE) were increased both in PAH patients and hypoxic PAH model rats. Knockdown of NDUFA4L2 decreased the levels of malondialdehyde (MDA) and 4-HNE in human PASMCs in hypoxia. Elevated MDA and 4-HNE levels might be associated with excessive ROS generation and increased expression of 5-lipoxygenase (5-LO) in hypoxia, but this effect was blocked by siNDUFA4L2. Further research found that p38-5-LO was a downstream signalling pathway of PASMCs proliferation induced by NDUFA4L2. Up-regulated NDUFA4L2 plays a critical role in the development of HPH, which mediates ROS production and proliferation of PASMCs, suggesting NDUFA4L2 as a potential new therapeutic target for PAH.  相似文献   

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Little is known about the human intra‐individual metabolic profile changes over an extended period of time. Here, we introduce a novel concept suggesting that children even at a very young age can be categorized in terms of metabolic state as they advance in development. The hidden Markov models were used as a method for discovering the underlying progression in the metabolic state. We applied the methodology to study metabolic trajectories in children between birth and 4 years of age, based on a series of samples selected from a large birth cohort study. We found multiple previously unknown age‐ and gender‐related metabolome changes of potential medical significance. Specifically, we found that the major developmental state differences between girls and boys are attributed to sphingolipids. In addition, we demonstrated the feasibility of state‐based alignment of personal metabolic trajectories. We show that children have different development rates at the level of metabolome and thus the state‐based approach may be advantageous when applying metabolome profiling in search of markers for subtle (patho)physiological changes.  相似文献   

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