RESUMO
Heritable pulmonary arterial hypertension (HPAH) is a rare type of pulmonary arterial hypertension that often presents with progressive exertional dyspnea and for which there is no significant effective drug. A HPAH patient was admitted to our hospital more than three years ago, and the gene mutation was bone morphogenetic protein 2 (BMPR2). For the first 45 months, she was given oral imatinib 100 mg once daily, and her symptoms and hemodynamics improved significantly, with no apparent side effects. It is reported that, in combination with the characteristics of the case and related literatures, it provides clinicians with other feasible treatment options for HPAH.
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Hipertensão Pulmonar , Humanos , Feminino , Hipertensão Pulmonar Primária Familiar/genética , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/genética , Mesilato de Imatinib/uso terapêutico , Mutação , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismoRESUMO
Objective: To monitor hemodynamic changes during serial balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension (CTEPH). Methods: General clinical data of CTEPH patients diagnosed from October 2017 to January 2022 in Beijing Chaoyang Hospital were collected, and 83 patients who underwent at least 1 BPA treatment were included to analyze their 6 min walking distance, WHO functional class, N-terminal B-type natriuretic peptide precursor (NT-proBNP), troponin I (cTnI) and haemodynamic indices. Baseline and follow-up after the final BPA clinical data and hemodynamics, functional status and serial hemodynamics before each series of BPA were collected to evaluate the efficacy of BPA for CTEPH patients. Complications and managements were documented to confirm the safety of BPA for CTEPH patients. Results: Three hundred and forty BPA procedures were performed in 83 CTEPH patients. The median number of BPA procedures was 4.0 and a total of 2104 vessels were dilated. In general, mPAP [from 50.0(42.0-55.25) mmHg(1 mmHg=0.133 kPa) to 32.0(27.0-42.0) mmHg, P<0.001], PVR[from (806.6±323.2) dyn·s·cm-5 to 420.0(295.0-613.5) dyn·s·cm-5, P<0.001] were significantly improved compared with baseline, but not CO and CI. Functional parameters including WHO functional class â /â ¡/â ¢/â £ (from 0/35/34/14 to 43/32/7/1, P<0.001), 6MWD [from 364.5(300.0-429.5)m to 461.0(409.0-501.0)m, P<0.001], NT-proBNP [from 1 357.0(232.0-2 715.0) ng/L to 141.0(57.0-627.8) ng/L,P<0.001] were significantly improved compared with baseline. A cumulative (compared to baseline) and serial (compared to preceding BPA session) analysis of the sequential BPA session confirmed that a major hemodynamic improvement in PVR and mPAP occurred in the first 3 serial BPA treatments. There was a dose-response relationship: the more segments that were treated, the greater were the subsequent reduction in PVR and mPAP. There were 32.0 complications (9.4%) associated with BPA procedures, and the most common complication was pulmonary hemorrhage caused by catheter-related vascular injury. Conclusions: BPA is an effective and safe alternative for technically non-operable CTEPH patients. The hemodynamic benefits of BPA in CTEPH patients were cumulative and correlated with the total number of vessels successfully dilated.
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Angioplastia com Balão , Hipertensão Pulmonar , Embolia Pulmonar , Humanos , Hipertensão Pulmonar/diagnóstico , Artéria Pulmonar , Embolia Pulmonar/diagnóstico , Angioplastia com Balão/métodos , Hemodinâmica , Doença Crônica , Resultado do TratamentoRESUMO
Objective: To analyze the efficacy and safety of Balloon Pulmonary Angioplasty (BPA) in patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH). Methods: A total of 38 CTEPH patients received at least one BPA treatment between February 2017 and April 2019 were enrolled. World Health Organization functional class(WHO-FC), 6-minute walking distance(6WMD), mean pulmonary artery pressure (mPAP), pulmonary vascular resistance(PVR), N-terminal pro brain natriuretic peptide(NT-proBNP) and echocardiographic indicators were collected at baseline and before each BPA procedure. Results: 38 patients received 95 times of BPA [ 2 (1, 4) times per person] totally. MPAP was 50 (43, 56) mmHg(1 mmHg=0.133 kPa) before BPA and 41(32, 50) mmHg after at least one BPA procedure, P<0.001. MPAP decreased from 50(42, 55) to 34(28, 49) mmHg (P=0.003) in 17 cases after 3-5 BPA procedures. In 15 cases, PVR decreased from 852(583, 1 140)dyn·s·cm-5 to 496(406, 802)dyn·s·cm-5, P=0.009. Besides, there were 13 patients with WHO Function Class â /â ¡ before BPA, 25 patients with â ¢/â £ class before BPA, 29 patients with â /â ¡ class after BPA treatment, and 9 patients with â ¢/â £ after BPA treatment, P<0.001. 6 WMD before and after BPA increased from 360(290, 442)m to 449(376, 505)m, P=0.015. The Meyer score of lung perfusion scanning got improved, from 0.54(0.53, 0.58) to 0.50(0.44, 0.58), P<0.001. Among all registered patients, 21 of whom NT-proBNP decreased from 1 285(606, 2 794) to 472(148, 745), P=0.014. The inner diameter of the right ventricular decreased from 54(41, 54)mm before surgery to 42(34, 49)mm after surgery, P<0.001. 6(6.3%, 6/95) complications occurred in 95 times of BPA. Conclusion: For inoperable patients with CTEPH, BPA can significantly improve disease severity, 6 MWD, heart function, decrease mPAP, PVR and improve lung perfusion, which is a safe and effective therapy.
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Angioplastia com Balão , Hipertensão Pulmonar/cirurgia , Embolia Pulmonar/cirurgia , Doença Crônica , Ecocardiografia , Humanos , Pulmão , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Objective: To analyze the clinical characteristics and the effect of targeted drug therapy of portopulmonary hypertension (PoPH). Methods: A total of 5 patients with PoPH who were admitted to the Department of Pulmonary and Critical Care Medicine of Beijing Chao-Yang Hospital from January 1, 2017 to December 31, 2018 were included. The clinical information and follow-up data were collected. The patient's medical history, clinical manifestations, right cardiac catheterization (RHC), classification of cardiac and hepatic function, treatment and prognosis were analyzed. Results: Among the 5 patients with PoPH, 3 were male and 2 were female. The median age was 56 years. The underlying diseases of portal hypertension were all cirrhosis, and 1 patient combined with hepatopulmonary syndrome (HPS). Dyspnea was the main respiratory symptom in all the 5 patients, and the median time from symptom onset to diagnosis was 1 year (5 months to 8 years). RHC was used as the diagnostic criteria for pulmonary hypertension in all patients, with a median mean pulmonary arterial pressure of 42 mmHg (1 mmHg=0.133 kPa) and a median pulmonary vascular resistance of 538 dyn·s·cm(-5). 3 cases were in Child-Pugh liver function grade B, and 2 were in grade A. The hepatic reserve function was not matched with the severity of cardiac insufficiency. Liver transplantation was performed in 1 patient, whose right ventricular dysfunction can be alleviated by targeted drug therapy after operation. All the 5 patients received targeted drug therapy of pulmonary hypertension. In the 3 patients who were regularly treated with targeted drugs and followed up on time, the cardiac function was improved during the follow-up period. There was no improvement or even deterioration of cardiac function in 2 patients who were not regularly treated or followed up. One patient died after liver transplantation. The cause of death was severe pneumonia and right ventricular dysfunction. The survival time after transplantation was 1 year. Conclusions: In PoPH patients, the hepatic reserve function is not matched with the heart function classification. PoPH can coexist with HPS. Regular application of pulmonary hypertension targeting drugs may benefit patients with PoPH.
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Síndrome Hepatopulmonar , Hipertensão Portal , Hipertensão Pulmonar , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Objective: To find key microRNA (miR) associated with chronic thromboembolic pulmonary hypertension (CTEPH). Methods: Affymetrix miR microarray data and GSE56914 data downloaded from GEO database (http: //www.ncbi.nlm.nih.gov/geo/) were obtained and integrated. The microarray data were obtained from peripheral blood samples of CTEPH patients and the matched control. Differentially expressed miRs were screened. Target genes of these miRs were searched. Then, functional enrichment analyses for these miRs were performed. After that, disease network including miRs, target genes and pathways was constructed. Results: Five important miRs including hsa-miR-885-5p, hsa-miR-501-5p, hsa-miR-615-3p, hsa-miR-610, and hsa-miR-346 were identified. Furthermore, hsa-miR-885-5p and hsa-miR-501-5p were significantly enriched in cell cycle pathway. Hsa-miR-615-3p was involved in cytokine-cytokine receptor interaction, axon guidance, focal adhesion and cell cycle pathway. Hsa-miR-610 was significantly enriched in focal adhesion pathway, and hsa-miR-346 was involved in cytokine-cytokine receptor interaction, axon guidance, and focal adhesion pathway. Conclusions: Hsa-miR-885-5p, hsa-miR-501-5p, hsa-miR-615-3p, hsa-miR-610 and hsa-miR-346 are important miRs for the development of CTEPH.
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Hipertensão Pulmonar , Adesão Celular , Humanos , MicroRNAsRESUMO
Objective: To compare the value of cardiac MRI (CMRI), ultrasonic cardiogram (UCG), multidetector CT (MDCT) in assessing right ventricular function (RV) in patients with PAH. Methods: A total of 31 consecutive patients with PAH (17 males and 14 females, 55±12 years) in Beijing Chao-Yang Hospital from August 2012 to February 2014 were prospectively enrolled. All patients underwent CMRI to get parameters including right ventricular end-systolic volume (ESV), end-diastolic dimension (EDV), stroke volume (SV), ejection fraction (EF), ventricular mass index (VMI). UCG parameters included Tei index, RV fractional area change (FAC), ESV, EDV. MDCT parameters included right /left ventricular internal diameter (RVd/LVd), right /left ventricular diastole maximum area (RVa/LVa), Cobb angle.These parameters obtained by MRI, UCG and MDCT were correlated with those of RHC respectively by Spearman or Pearson correlation analysis. Results: Six minutes walk distance had moderate negative correlation with CMRI-EF (40±9), VMI 44-115(71±20) g/m(2,) Cobb angle(67°±12°); RHC-SV had moderate negative correlation with CMRI-SV(57±21) ml, EF, VMI, UCG-EF(41±14), Tei(0.82±0.29), FAC(30±9), RVd(45±7) mm, RVa(2 484±596) mm(2), Cobb angle ; Right cardiac work index had moderate negative correlation with CMRI-EF, RVd and Cobb angle. Conclusions: MRI-EF is the best parameter to reflect RV function. CMRI is the optimal method to assess RV function, and then is the MDCT and the last is UCG.
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Artéria Pulmonar , Função Ventricular Direita , Adulto , Idoso , Cateterismo Cardíaco , Feminino , Humanos , Hipertensão , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Volume Sistólico , Tomografia Computadorizada por Raios X , UltrassomRESUMO
Objective: To investigate the diagnostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin â (TnI) for detecting right ventricular dysfunction (RVD) in patients with non-high-risk acute pulmonary thromboembolism (APE). Methods: A retrospective analysis was performed in 96 adult patients [44 males, 52 females, aged (61±14) years] with non-high-risk APE from January 2015 to June 2016. All patients were divided into RVD group and non-RVD group according to whether there was right ventricular enlargement on echocardiography. The baseline data, serumTnI and NT-proBNP levels were compared between the 2 groups and the diagnostic value of the 2 cardiac markers for RVD was analyzed. Results: There were no significant differences in age, gender, body mass index between the 2 groups (P>0.05). The creatinine clearance rate of the RVD group was lower than that of the non-RVD group [96.4 (77.5,99.6) vs 101.7 (95.1,106.5), P=0.021]. NT-proBNP [2 300 (1 056,3 396) vs 188 (61,535), P<0.01] and TnI [0.13 (0.09,0.25) vs 0.00 (0.00,0.02), P<0.01] were significant higher in the RVD group than in the non-RVD group. The univariate logistic regression analyses showed that NT-proBNP (per 100 ng/L, OR 1.199, 95%CI 1.117-1.287), TnI (per 0.01 µg/L, OR 1.164, 95%CI 1.079-1.256) and creatinine clearance rate (OR 0.968, 95% CI 0.938-0.998) were significantly associated with RVD. Multivariate regression analysis showed that NT-proBNP (per 100 ng/L, OR 1.155, 95%CI 1.074-1.241) and TnI (per 0.01 µg/L, OR 1.079, 95% CI 1.011-1.151) were independently associated with RVD. The areas under the ROC curve (AUC) of NT-proBNP, TnI, and the combination of them were 0.908 (95% CI 0.841-0.976), 0.896 (95% CI 0.826-0.966) and 0.925 (95% CI 0.862-0.988), respectively. The cut-off value of NT-proBNP was 503.5 ng/L, with a sensitivity of 85.7%, specificity of 75.4%, positive predictive value (PPV) of 66.7% and negative predictive value (NPV) of 90.2%.The cut-off value of TnI was 0.05 µg/L, and the sensitivity, specificity, PPV and NPV was 80.0%, 86.9%, 77.8% and 88.3%, respectively. The optimal probability derived from the logistic regression model in which the 2 biomarkers were the independent variables was 0.779, with a sensitivity, specificity, PPV and NPV of 65.7%, 96.7%, 92.0%, 83.1%, respectively. Conclusion: Both NT-proBNP and TnI had preferably good diagnostic value for RVD in patients with non-high-risk APE, but their clinical application needed comprehensive evaluation combined with the overall manifestations of the patients and experimental methods. The diagnostic value was higher when the 2 biomarkers were evaluated together.
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Peptídeo Natriurético Encefálico , Embolia Pulmonar , Disfunção Ventricular Direita , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/metabolismo , Embolia Pulmonar/sangue , Curva ROC , Estudos Retrospectivos , Troponina I/sangue , Disfunção Ventricular Direita/sangueRESUMO
Objective: To analyze the clinical features of 3 cases of Takayasu arteritis(TA) with pulmonary cavities on chest computed tomography(CT). Methods: The clinical data of 3 TA patients with cavities on the chest CT who were admitted into Beijing Chaoyang Hospital were retrospectively analyzed. A literature search was performed with "Takayasu arteritis" and "pulmonary" as the key words in China Knowledge Resource Intergrated Database (CNKI) and Pubmed Database for publications from Jan 1, 2000 to Dec. 31,2017. The relevant literatures were reviewed. Results: Among the 3 patients, 2 were males and 1 was female, aging 49, 28 and 28 years, respectively. They presented with cough, fever and chest pain, and chest CT showed cavities, single or multiple, either with thick or thin wall, or wedge-shaped consolidation, residual stripes after being absorbed, and one case had pulmonary biopsy results which showed hemorrhagic infarction. They were all misdiagnosed before as pneumonia, pulmonary tuberculosis, pulmonary thromboembolism. After being treated by combination therapy of glucocorticoids and immunosuppressive agents, the disease improved significantly. A total of 777 cases with TA involving pulmonary arteries were reported, from which 13 cases with involvement of pulmonary parenchyma were described. Therefore total 16 cases including the 3 cases in this article were included for analysis. Twelve cases showed patchy or wedge-shaped ground-glass opacity and consolidation, and peripheral lung stripes remained after being absorbed. Two cases showed pleural effusion, and 4 cases showed cavities, 3 cases were misdiagnosed as pulmonary tuberculosis, 7 as pulmonary infection, and 5 as pulmonary thromboembolism. Conclusions: TA with pulmonary arteries involved is susceptible to be misdiagnosed and missed, and therefore, in patients with cough, hemoptysis, chest pain and cavities in pulmonary parenchyma, TA should be suspected. Early diagnosis and appropriate treatment can lead to a better prognosis.
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Hipertensão Pulmonar/complicações , Artéria Pulmonar/fisiopatologia , Arterite de Takayasu/complicações , Tomografia Computadorizada por Raios X , Adulto , China , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/diagnóstico por imagem , Estudos Retrospectivos , Arterite de Takayasu/diagnóstico por imagem , Arterite de Takayasu/fisiopatologiaRESUMO
Objective: To analyze the differential gene expression of patients with idiopathic pulmonary fibrosis and pulmonary hypertension (IPF-PH). Methods: The expression profile data of GSE15197 was downloaded from the Gene Expression Omnibus (GEO) database. Bonferroni algorithm was used to identify the differentially expressed genes of pulmonary tissues from IPF-PH, idiopathic pulmonary arterial hypertension (IPAH) and Normal groups. Principal component analysis was used to extract the principal components of three types of samples and differentially expressed genes were obtained. Gene annotation and gene association analysis were used to analyze gene function and related signaling pathways. Results: Gene expression profiles of pulmonary tissues from IPF-PH, IPAH and Normal groups were compared and analyzed, and 160 differentially expressed genes were found (P<0.05). Nine principal component were found with the cumulative contribution rate of >0.85, and there were 44 significant differences genes with the loading coefficient >80% in principal component one, which was mainly related to the expression of cilium, gamma-glutamyltransferase, and phospholipase. The signaling pathway of differential expression genes were mainly involved in the biosynthesis of leukotriene biosynthetic process and gamma-glutamyltransferase activity. Conclusion: The differential gene expression and their functional annotation can provide important clues for the pathogenic genes of IPF-PH, and may provide a theoretical basis for exploring potential biomarkers and drug targets.
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Perfilação da Expressão Gênica , Hipertensão Pulmonar/genética , Fibrose Pulmonar Idiopática/genética , Testes Genéticos , Humanos , Hipertensão Pulmonar/complicações , Fibrose Pulmonar Idiopática/complicações , Pulmão , TranscriptomaRESUMO
OBJECTIVE: To enhance the understanding of Takayasu's arteritis with pulmonary vascular involvement through the analyses on clinical features, imaging findings, misdiagnoses and treatments. METHODS: A retrospective study was conducted to analyze the clinical records of patients diagnosed as Takayasu's arteritis with pulmonary vascular involvement admitted to Beijing Chaoyang Hospital from January 2004 to December 2014. RESULTS: In recent 10 years, there were 90 patients diagnosed as Takayasu's arteritis in Beijing Chaoyang Hospital, 33 of them were involved with pulmonary arterial, which account for 36.7%, while 12 cases were involved with pulmonary arteries alone, which account for 13.3% of all. Among the 33 patients, dyspnea (23 cases, 69.7%) was the most common symptom, followed by hemoptysis (19 cases, 57.6%) and Vascular murmur (23 cases, 69.7%), pleural effusion (8 cases, 24.2%), unequal blood pressure of upper limbs (4 cases, 12.1%) were the main signs. The diagnostic time varied significantly, from 1 month to 10 years. 21 patients were misdiagnosed and the misdiagnosis rate was 63.6%. CONCLUSION: Takayasu's arteritis with pulmonary vascular involvement is not rare. The clinical manifestation of Takayasu's arteritis is unspecific and misdiagnosis rate is relatively high. Therefore, we should raise awareness of Takayasu's arteritis and detailed clinical examination will be helpful to reduce the misdiagnosis rate.
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Arterite de Takayasu/diagnóstico , Pressão Sanguínea , Erros de Diagnóstico , Dispneia/complicações , Hemoptise/complicações , Humanos , Derrame Pleural/complicações , Artéria Pulmonar/fisiopatologia , Estudos Retrospectivos , Arterite de Takayasu/fisiopatologiaRESUMO
OBJECTIVE: This study sought to explore endothelial nitric oxide synthase (eNOS) expression in acute pulmonary thromboembolism (APE). MATERIALS AND METHODS: eNOS expression in lung tissue and bone marrow-derived endothelial progenitor cells (BM-EPCs) from APE mouse models was assessed by immunohistochemistry and real-time PCR. A gene expression profile meta-analysis was performed on human venous thromboembolism (VTE) whole blood samples recorded in the Gene Expression Omnibus (GEO) repository. Significantly expressed genes were determined from the microarray data by unsupervised clustering and supervised classification. Selected sample data with significantly expressed genes were further analyzed by principal component analysis (PCA), followed by Bayesian probit regression. Key discriminate genes were further grouped and annotated using functional annotations and gene enrichments using the online Database for Annotation, Visualization and Integrated Discovery (DAVID) software (v. 6.7). RESULTS: While eNOS expression was significantly higher, serum nitric oxide levels were significantly lower in APE mice (20.42 ± 2.15 µM) compared to controls (53.50 ± 5.69 µM, p<0.001). eNOS mRNA and protein levels were significantly upregulated in BM-EPCs from APE mice. GEO repository data reported 3,397 upregulated and 4,173 downregulated genes (including eNOS) in VTE patients. In this regression analysis, the significant principal component PC1 and PC2 (p<0.05) were useful in distinguishing the VTE classification. The coefficient value of eNOS was -0.47707 in PC1 and -0.08429 in PC2, which did have some proportions on these significantly discriminated components but did not contribute significantly to the VTE classification. Functional enrichment in terms of acetylation and phosphoproteins were high. CONCLUSIONS: Our findings, therefore, suggest that expression of eNOS is significantly altered in APE and may be a potential peripheral blood biomarker. Modulation of eNOS expression may be used for APE treatment.
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Óxido Nítrico Sintase Tipo III/metabolismo , Embolia Pulmonar/enzimologia , Animais , Teorema de Bayes , Biologia Computacional , Humanos , Camundongos , Óxido Nítrico/sangue , Óxido Nítrico Sintase Tipo III/genética , Análise de Sequência com Séries de Oligonucleotídeos , Embolia Pulmonar/genética , Células-Tronco/metabolismo , TranscriptomaRESUMO
MicroRNAs have been shown to play an important role in normal hematopoisis and leukemogenesis. Here, we report function and mechanisms of miR-181 family in myeloid differentiation and acute myeloid leukemia (AML). The aberrant overexpression of all the miR-181 family members (miR-181a/b/c/d) was detected in French-American-British M1, M2 and M3 subtypes of adult AML patients. By conducting gain- and loss-of-function experiments, we demonstrated that miR-181a inhibits granulocytic and macrophage-like differentiation of HL-60 cells and CD34+ hematopoietic stem/progenitor cells (HSPCs) by directly targeting and downregulating the expression of PRKCD (which then affected the PRKCD-P38-C/EBPα pathway), CTDSPL (which then affected the phosphorylation of retinoblastoma protein) and CAMKK1. The three genes were also demonstrated to be the targets of miR-181b, miR-181c and miR-181d, respectively. Significantly decreases in the expression levels of the target proteins were detected in AML patients. Inhibition of the expression of miR-181 family members owing to Lenti-miRZip-181a infection in bone marrow blasts of AML patients increased target protein expression levels and partially reversed myeloid differentiation blockage. In the mice implanted with AML CD34+ HSPCs, expression inhibition of the miR-181 family by Lenti-miRZip-181a injection improved myeloid differentiation, inhibited engraftment and infiltration of the leukemic CD34+ cells into the bone marrow and spleen, and released leukemic symptoms. In conclusion, our findings revealed new mechanism of miR-181 family in normal hematopoiesis and AML development, and suggested that expression inhibition of the miR-181 family could provide a new strategy for AML therapy.
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Diferenciação Celular , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , MicroRNAs/genética , Terapia de Alvo Molecular , Células Mieloides/patologia , Animais , Sequência de Bases , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Bovinos , Diferenciação Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Granulócitos/efeitos dos fármacos , Granulócitos/patologia , Células HL-60 , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Células Mieloides/efeitos dos fármacos , Proteína Quinase C-delta/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Acetato de Tetradecanoilforbol/farmacologia , Transdução Genética , Tretinoína/farmacologia , Proteínas Supressoras de Tumor/genéticaRESUMO
Abnormal proliferation, apoptosis repression and differentiation blockage of hematopoietic stem/progenitor cells have been characterized to be the main reasons leading to acute myeloid leukemia (AML). Previous studies showed that miR-29a and miR-29b could function as tumor suppressors in leukemogenesis. However, a comprehensive investigation of the function and mechanism of miR-29 family in AML development and their potentiality in AML therapy still need to be elucidated. Herein, we reported that the family members, miR-29a, -29b and -29c, were commonly downregulated in peripheral blood mononuclear cells and bone marrow (BM) CD34+ cells derived from AML patients as compared with the healthy donors. Overexpression of each miR-29 member in THP1 and NB4 cells markedly inhibited cell proliferation and promoted cell apoptosis. AKT2 and CCND2 mRNAs were demonstrated to be targets of the miR-29 members, and the role of miR-29 family was attributed to the decrease of Akt2 and CCND2, two key signaling molecules. Significantly increased Akt2, CCND2 and c-Myc levels in the AML cases were detected, which were correlated with the decreased miR-29 expression in AML blasts. Furthermore, a feed-back loop comprising of c-Myc, miR-29 family and Akt2 were found in myeloid leukemogenesis. Reintroduction of each miR-29 member partially corrected abnormal cell proliferation and apoptosis repression and myeloid differentiation arrest in AML BM blasts. An intravenous injection of miR-29a, -29b and -29c in the AML model mice relieved leukemic symptoms significantly. Taken together, our finding revealed a pivotal role of miR-29 family in AML development and rescue of miR-29 family expression in AML patients could provide a new therapeutic strategy.