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1.
Sci Adv ; 10(3): eadk6524, 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38241373

RESUMO

Pulmonary hypertension (PH) can affect both pulmonary arterial tree and cardiac function, often leading to right heart failure and death. Despite the urgency, the lack of understanding has limited the development of effective cardiac therapeutic strategies. Our research reveals that MCJ modulates mitochondrial response to chronic hypoxia. MCJ levels elevate under hypoxic conditions, as in lungs of patients affected by COPD, mice exposed to hypoxia, and myocardium from pigs subjected to right ventricular (RV) overload. The absence of MCJ preserves RV function, safeguarding against both cardiac and lung remodeling induced by chronic hypoxia. Cardiac-specific silencing is enough to protect against cardiac dysfunction despite the adverse pulmonary remodeling. Mechanistically, the absence of MCJ triggers a protective preconditioning state mediated by the ROS/mTOR/HIF-1α axis. As a result, it preserves RV systolic function following hypoxia exposure. These discoveries provide a potential avenue to alleviate chronic hypoxia-induced PH, highlighting MCJ as a promising target against this condition.


Assuntos
Hipertensão Pulmonar , Animais , Humanos , Camundongos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/tratamento farmacológico , Hipóxia , Pulmão , Miocárdio , Artéria Pulmonar , Suínos
2.
Biomedicines ; 11(7)2023 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-37509463

RESUMO

INTRODUCTION: In stable patients with pulmonary arterial hypertension (PAH), pulmonary rehabilitation (PR) is an effective, safe and cost-effective non-pharmacological treatment. However, the effects of PR on vascular function have been poorly explored. This study aimed to compare the amounts of circulating progenitor cells (PCs) and endothelial microvesicles (EMVs) in patients with PAH before and after 8 weeks of endurance exercise training as markers of vascular competence. METHODS: A prospective study of 10 consecutive patients with PAH that successfully finished a PR program (8 weeks) was carried out before and after this intervention. Levels of circulating PCs defined as CD34+CD45low progenitor cells and levels of EMVs (CD31+ CD42b-) were measured by flow cytometry. The ratio of PCs to EMVs was taken as a measure of the balance between endothelial damage and repair capacity. RESULTS: All patients showed training-induced increases in endurance time (mean change 287 s). After PR, the number of PCs (CD34+CD45low/total lymphocytes) was increased (p < 0.05). In contrast, after training, the level of EMVs (CD31+ CD42b-/total EMVs) was reduced. The ratio of PCs to EMVs was significantly higher after training (p < 0.05). CONCLUSION: Our study shows, for the first time, that endurance exercise training in patients with stable PAH has a positive effect, promoting potential mechanisms of damage/repair in favor of repair. This effect could contribute to a positive hemodynamic and clinical response.

3.
Sci Rep ; 11(1): 18797, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34552142

RESUMO

Pulmonary endarterectomy (PEA) resected material offers a unique opportunity to develop an in vitro endothelial cell model of chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to comprehensively analyze the endothelial function, molecular signature, and mitochondrial profile of CTEPH-derived endothelial cells to better understand the pathophysiological mechanisms of endothelial dysfunction behind CTEPH, and to identify potential novel targets for the prevention and treatment of the disease. Isolated cells from specimens obtained at PEA (CTEPH-EC), were characterized based on morphology, phenotype, and functional analyses (in vitro and in vivo tubule formation, proliferation, apoptosis, and migration). Mitochondrial content, morphology, and dynamics, as well as high-resolution respirometry and oxidative stress, were also studied. CTEPH-EC displayed a hyperproliferative phenotype with an increase expression of adhesion molecules and a decreased apoptosis, eNOS activity, migration capacity and reduced angiogenic capacity in vitro and in vivo compared to healthy endothelial cells. CTEPH-EC presented altered mitochondrial dynamics, increased mitochondrial respiration and an unbalanced production of reactive oxygen species and antioxidants. Our study is the foremost comprehensive investigation of CTEPH-EC. Modulation of redox, mitochondrial homeostasis and adhesion molecule overexpression arise as novel targets and biomarkers in CTEPH.


Assuntos
Endotélio Vascular/citologia , Hipertensão Pulmonar/patologia , Embolia Pulmonar/patologia , Apoptose , Estudos de Casos e Controles , Doença Crônica , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/patologia , Estresse Oxidativo , Artéria Pulmonar/citologia , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Embolia Pulmonar/fisiopatologia
4.
Cells ; 10(7)2021 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-34359858

RESUMO

BACKGROUND: Endothelial dysfunction is central to PAH. In this study, we simultaneously analysed circulating levels of endothelial microvesicles (EMVs) and progenitor cells (PCs) in PAH and in controls, as biomarkers of pulmonary endothelial integrity and evaluated differences among PAH subtypes and as a response to treatment. METHODS: Forty-seven controls and 144 patients with PAH (52 idiopathic, 9 heritable, 31 associated with systemic sclerosis, 15 associated with other connective tissue diseases, 20 associated with HIV and 17 associated with portal hypertension) were evaluated. Forty-four patients with scleroderma and 22 with HIV infection, but without PAH, were also studied. Circulating levels of EMVs, total (CD31+CD42b-) and activated (CD31+CD42b-CD62E+), as well as circulating PCs (CD34+CD133+CD45low) were measured by flow cytometry and the EMVs/PCs ratio was computed. In treatment-naïve patients, measurements were repeated after 3 months of PAH therapy. RESULTS: Patients with PAH showed higher numbers of EMVs and a lower percentage of PCs, compared with healthy controls. The EMV/PC ratio was increased in PAH patients, and in patients with SSc or HIV without PAH. After starting PAH therapy, individual changes in EMVs and PCs were variable, without significant differences being observed as a group. Conclusion: PAH patients present disturbed vascular homeostasis, reflected in changes in circulating EMV and PC levels, which are not restored with PAH targeted therapy. Combined measurement of circulating EMVs and PCs could be foreseen as a potential biomarker of endothelial dysfunction in PAH.


Assuntos
Biomarcadores/metabolismo , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/metabolismo , Estudos de Casos e Controles , Micropartículas Derivadas de Células/metabolismo , Células Endoteliais/metabolismo , Feminino , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Hipertensão Arterial Pulmonar/patologia , Hipertensão Arterial Pulmonar/fisiopatologia , Células-Tronco/metabolismo , Resultado do Tratamento
6.
Sci Rep ; 11(1): 5583, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33692478

RESUMO

Chronic thromboembolic pulmonary hypertension (CTEPH) is a vascular disease characterized by the presence of organized thromboembolic material in pulmonary arteries leading to increased vascular resistance, heart failure and death. Dysfunction of endothelial cells is involved in CTEPH. The present study describes for the first time the molecular processes underlying endothelial dysfunction in the development of the CTEPH. The advanced analytical approach and the protein network analyses of patient derived CTEPH endothelial cells allowed the quantitation of 3258 proteins. The 673 differentially regulated proteins were associated with functional and disease protein network modules. The protein network analyses resulted in the characterization of dysregulated pathways associated with endothelial dysfunction, such as mitochondrial dysfunction, oxidative phosphorylation, sirtuin signaling, inflammatory response, oxidative stress and fatty acid metabolism related pathways. In addition, the quantification of advanced oxidation protein products, total protein carbonyl content, and intracellular reactive oxygen species resulted increased attesting the dysregulation of oxidative stress response. In conclusion this is the first quantitative study to highlight the involvement of endothelial dysfunction in CTEPH using patient samples and by network medicine approach.


Assuntos
Células Endoteliais/metabolismo , Hipertensão Pulmonar/metabolismo , Carbonilação Proteica , Mapas de Interação de Proteínas , Artéria Pulmonar/metabolismo , Embolia Pulmonar/metabolismo , Tromboembolia/metabolismo , Células Endoteliais/patologia , Humanos , Hipertensão Pulmonar/patologia , Artéria Pulmonar/patologia , Embolia Pulmonar/patologia , Tromboembolia/patologia
7.
Am J Respir Cell Mol Biol ; 64(4): 407-415, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33180562

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new strain of a Coronaviridae virus that presents 79% genetic similarity to the severe acute respiratory syndrome coronavirus, has been recently recognized as the cause of a global pandemic by the World Health Organization, implying a major threat to world public health. SARS-CoV-2 infects host human cells by binding through the viral spike proteins to the ACE-2 (angiotensin-converting enzyme 2) receptor, fuses with the cell membrane, enters, and starts its replication process to multiply its viral load. Coronavirus disease (COVID-19) was initially considered a respiratory infection that could cause pneumonia. However, in severe cases, it extends beyond the respiratory system and becomes a multiorgan disease. This transition from localized respiratory infection to multiorgan disease is due to two main complications of COVID-19. On the one hand, it is due to the so-called cytokine storm: an uncontrolled inflammatory reaction of the immune system in which defensive molecules become aggressive for the body itself. On the other hand, it is due to the formation of a large number of thrombi that can cause myocardial infarction, stroke, and pulmonary embolism. The pulmonary endothelium actively participates in these two processes, becoming the last barrier before the virus spreads throughout the body. In this review, we examine the role of the pulmonary endothelium in response to COVID-19, the existence of potential biomarkers, and the development of novel therapies to restore vascular homeostasis and to protect and/or treat coagulation, thrombosis patients. In addition, we review the thrombotic complications recently observed in patients with COVID-19 and its potential threatening sequelae.


Assuntos
COVID-19/metabolismo , Endotélio/metabolismo , Embolia Pulmonar/metabolismo , SARS-CoV-2/metabolismo , Trombose/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Biomarcadores/metabolismo , COVID-19/patologia , COVID-19/terapia , Endotélio/patologia , Endotélio/virologia , Humanos , Fusão de Membrana , Embolia Pulmonar/patologia , Embolia Pulmonar/terapia , Embolia Pulmonar/virologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Trombose/patologia , Trombose/terapia , Trombose/virologia
9.
Am J Physiol Lung Cell Mol Physiol ; 317(2): L222-L234, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31166128

RESUMO

We have analyzed the effect of the soluble guanylate cyclase (sGC) stimulator BAY 41-2272 in a therapeutic intervention in guinea pigs chronically exposed to cigarette smoke (CS). The effects of sGC stimulation on respiratory function, pulmonary hemodynamics, airspace size, vessel remodeling, and inflammatory cell recruitment to the lungs were evaluated in animals that had been exposed to CS for 3 mo. CS exposure was continued for an additional 3 mo in half of the animals and withdrawn in the other half. Animals that stopped CS exposure had slightly lower pulmonary artery pressure (PAP) and right ventricle (RV) hypertrophy than those who continued CS exposure, but they did not recover from the emphysema and the inflammatory cell infiltrate. Conversely, oral BAY 41-2272 administration stopped progression or even reversed the CS-induced emphysema in both current and former smokers, respectively. Furthermore, BAY 41-2272 produced a reduction in the RV hypertrophy, which correlated with a decrease in the PAP values. By contrast, the degree of vessel remodeling induced by CS remained unchanged in the treated animals. Functional network analysis suggested perforin/granzyme pathway downregulation as an action mechanism capable of stopping the progression of emphysema after sGC stimulation. The pathway analysis also showed normalization of the expression of cGMP-dependent serine/kinases. In conclusion, in guinea pigs chronically exposed to CS, sGC stimulation exerts beneficial effects on the lung parenchyma and the pulmonary vasculature, suggesting that sGC stimulators might be a potential alternative for chronic obstructive pulmonary disease treatment that deserves further evaluation.


Assuntos
Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Enfisema Pulmonar/tratamento farmacológico , Fumaça , Guanilil Ciclase Solúvel/uso terapêutico , Animais , Guanilato Ciclase/metabolismo , Cobaias , Hipertensão Pulmonar/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Enfisema Pulmonar/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Nicotiana , Vasodilatadores/farmacologia
10.
Eur Respir J ; 54(2)2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31196942

RESUMO

BACKGROUND: Exposure to cigarette smoke has been shown to lead to vascular remodelling. Computed tomography (CT) imaging measures of vascular pruning have been associated with pulmonary vascular disease, an important morbidity associated with smoking. In this study we compare CT-based measures of distal vessel loss to histological vascular and parenchymal changes. METHODS: A retrospective review of 80 patients who had undergone lung resection identified patients with imaging appropriate for three-dimensional (3D) vascular reconstruction (n=18) and a second group for two-dimensional (2D) analysis (n=19). Measurements of the volume of the small vessels (3D) and the cross-sectional area of the small vessels (<5 mm2 cross-section) were computed. Histological measures of cross-sectional area of the vasculature and loss of alveoli septa were obtained for all subjects. RESULTS: The 2D cross-sectional area of the vasculature on CT imaging was associated with the histological vascular cross-sectional area (r=0.69; p=0.001). The arterial small vessel volume assessed by CT correlated with the histological vascular cross-sectional area (r=0.50; p=0.04), a relationship that persisted even when adjusted for CT-derived measures of emphysema in a regression model. CONCLUSIONS: Loss of small vessel volume in CT imaging of smokers is associated with histological loss of vascular cross-sectional area. Imaging-based quantification of pulmonary vasculature provides a noninvasive method to study the multiscale effects of smoking on the pulmonary circulation.


Assuntos
Veias Pulmonares/diagnóstico por imagem , Veias Pulmonares/patologia , Idoso , Artefatos , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Pulmão/patologia , Masculino , Microcirculação , Pessoa de Meia-Idade , Enfisema Pulmonar/diagnóstico por imagem , Análise de Regressão , Testes de Função Respiratória , Estudos Retrospectivos , Fumar/efeitos adversos , Tomografia Computadorizada por Raios X , Remodelação Vascular
11.
Respir Res ; 20(1): 74, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992021

RESUMO

BACKGROUND: Pulmonary vascular abnormalities are a characteristic feature of chronic obstructive pulmonary disease (COPD). Cigarette smoking is the most important risk factor for COPD. It is believed that its constant exposure triggers endothelial cell damage and vascular remodelling. Under pathological conditions, progenitor cells (PCs) are mobilized from the bone marrow and recruited to sites of vascular injury. The aim of the study was to investigate whether in COPD the number of circulating PCs is related to the presence of bone marrow-derived cells in pulmonary arteries and the association of these phenomena to both systemic and pulmonary endothelial dysfunction. METHODS: Thirty-nine subjects, 25 with COPD, undergoing pulmonary resection because of a localized carcinoma, were included. The number of circulating PCs was assessed by flow cytometry using a triple combination of antibodies against CD45, CD133 and CD34. Infiltrating CD45+ cells were identified by immunohistochemistry in pulmonary arteries. Endothelial function in systemic and pulmonary arteries was measured by flow-mediated dilation and adenosine diphosphate-induced vasodilation, respectively. RESULTS: COPD patients had reduced numbers of circulating PCs (p < 0.05) and increased numbers of CD45+ cells (< 0.05) in the pulmonary arterial wall than non-COPD subjects, being both findings inversely correlated (r = - 0.35, p < 0.05). In pulmonary arteries, the number of CD45+ cells correlated with the severity of vascular remodelling (r = 0.4, p = 0.01) and the endothelium-dependent vasodilation (r = - 0.3, p = 0.05). Systemic endothelial function was unrelated to the number of circulating PCs and changes in pulmonary vessels. CONCLUSION: In COPD, the decrease of circulating PCs is associated with their recruitment in pulmonary arteries, which in turn is associated with endothelial dysfunction and vessel remodelling, suggesting a mechanistic link between these phenomena. Our findings are consistent with the notion of an imbalance between endothelial damage and repair capacity in the pathogenesis of pulmonary vascular abnormalities in COPD.


Assuntos
Movimento Celular/fisiologia , Endotélio Vascular/metabolismo , Artéria Pulmonar/metabolismo , Doença Pulmonar Obstrutiva Crônica/sangue , Células-Tronco/metabolismo , Idoso , Endotélio Vascular/patologia , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/patologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Células-Tronco/patologia
12.
Am J Respir Cell Mol Biol ; 59(4): 490-499, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29757677

RESUMO

Pulmonary vascular remodeling is an angiogenic-related process involving changes in smooth muscle cell (SMC) homeostasis, which is frequently observed in chronic obstructive pulmonary disease (COPD). MicroRNAs (miRNAs) are small, noncoding RNAs that regulate mRNA expression levels of many genes, leading to the manifestation of cell identity and specific cellular phenotypes. Here, we evaluate the miRNA expression profiles of pulmonary arteries (PAs) of patients with COPD and its relationship with the regulation of SMC phenotypic change. miRNA expression profiles from PAs of 12 patients with COPD, 9 smokers with normal lung function (SK), and 7 nonsmokers (NS) were analyzed using TaqMan Low-Density Arrays. In patients with COPD, expression levels of miR-98, miR-139-5p, miR-146b-5p, and miR-451 were upregulated, as compared with NS. In contrast, miR-197, miR-204, miR-485-3p, and miR-627 were downregulated. miRNA-197 expression correlated with both airflow obstruction and PA intimal enlargement. In an in vitro model of SMC differentiation, miR-197 expression was associated with an SMC contractile phenotype. miR-197 inhibition blocked the acquisition of contractile markers in SMCs and promoted a proliferative/migratory phenotype measured by both cell cycle analysis and wound-healing assay. Using luciferase assays, Western blot, and quantitative PCR, we confirmed that miR-197 targets the transcription factor E2F1. In PAs from patients with COPD, levels of E2F1 were increased as compared with NS. In PAs of patients with COPD, remodeling of the vessel wall is associated with downregulation of miR-197, which regulates SMC phenotype. The effect of miR-197 on PAs might be mediated, at least in part, by the key proproliferative factor, E2F1.


Assuntos
Regulação da Expressão Gênica , MicroRNAs/genética , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Remodelação Vascular/genética , Idoso , Diferenciação Celular/genética , Proliferação de Células/genética , Fator de Transcrição E2F1/metabolismo , Feminino , Volume Expiratório Forçado , Redes Reguladoras de Genes , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Índice de Gravidade de Doença
13.
PLoS One ; 13(4): e0195724, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29672621

RESUMO

BACKGROUND: Circulating endothelial microparticles (EMPs) and progenitor cells (PCs) are biological markers of endothelial function and endogenous repair capacity. The study was aimed to investigate whether COPD patients have an imbalance between EMPs to PCs compared to controls and to evaluate the effect of cigarette smoke on these circulating markers. METHODS: Circulating EMPs and PCs were determined by flow cytometry in 27 nonsmokers, 20 smokers and 61 COPD patients with moderate to severe airflow obstruction. We compared total EMPs (CD31+CD42b-), apoptotic if they co-expressed Annexin-V+ or activated if they co-expressed CD62E+, circulating PCs (CD34+CD133+CD45+) and the EMPs/PCs ratio between groups. RESULTS: COPD patients presented increased levels of total and apoptotic circulating EMPs, and an increased EMPs/PCs ratio, compared with nonsmokers. Women had less circulating PCs than men through all groups and those with COPD showed lower levels of PCs than both control groups. In smokers, circulating EMPs and PCs did not differ from nonsmokers, being the EMPs/PCs ratio in an intermediate position between COPD and nonsmokers. CONCLUSIONS: We conclude that COPD patients present an imbalance between endothelial damage and repair capacity that might explain the frequent concurrence of cardiovascular disorders. Factors related to the disease itself and gender, rather than cigarette smoking, may account for this imbalance.


Assuntos
Micropartículas Derivadas de Células/patologia , Endotélio Vascular/patologia , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/patologia , Idoso , Apoptose , Estudos de Casos e Controles , Micropartículas Derivadas de Células/fisiologia , Células Progenitoras Endoteliais/patologia , Células Progenitoras Endoteliais/fisiologia , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Regeneração/fisiologia , Testes de Função Respiratória , Fumar/sangue , Fumar/patologia , Fumar/fisiopatologia
14.
PLoS One ; 13(1): e0190628, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29304131

RESUMO

OBJECTIVE: Soluble guanylate cyclase (sGC) is a key enzyme of the nitric oxide-cyclic guanosine 3',5'-monophosphate (NO-cGMP) signaling pathway, and its pharmacological stimulation has been shown to prevent the development of emphysema and pulmonary vascular remodeling in animal models of chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate the effects of sGC stimulation on oxidative stress in the plasma of guinea pigs chronically exposed to cigarette smoke (CS). METHODS AND RESULTS: Guinea pigs were exposed to CS or sham for three months, and received either the sGC stimulator BAY 41-2272 or vehicle. Body weight was measured weekly; and markers of oxidative stress in plasma, and airspace size and inflammatory cell infiltrate in lung tissue were analyzed at the end of the study. Compared to sham-exposed guinea pigs, CS-exposed animals gained less body weight and showed higher plasma levels of nitrated tyrosine residues (3-NT), 4-hydroxynonenal (4-HNE), and 8-hydroxydeoxyguanosine (8-OHdG). Treatment with the sGC stimulator led to a body weight gain in the CS-exposed guinea pigs similar to non-exposed and attenuated the increase in 3-NT and 4-HNE. Plasma levels of 3-NT correlated with the severity of inflammatory cell infiltrate in the lung. CONCLUSION: Stimulation of sGC prevents oxidative stress induced by CS exposure and is associated with an attenuated inflammatory response in the lung.


Assuntos
Estresse Oxidativo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Animais , Biomarcadores/sangue , Fumar Cigarros , Ativação Enzimática , Cobaias , Pulmão/enzimologia , Pulmão/metabolismo , Masculino , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/enzimologia , Fumaça
15.
Respir Res ; 18(1): 50, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28330488

RESUMO

BACKGROUND: Cigarette smoke (CS) is associated with lower numbers of circulating stem cells and might severely affect their mobilization, trafficking and homing. Our study was designed to demonstrate in an animal model of CS exposure whether CS affects the homing and functional capabilities of bone marrow-derived mesenchymal stem cells (BM-MSCs). METHODS: Guinea pigs (GP), exposed or sham-exposed to CS, were administered via tracheal instillation or by vascular administration with 2.5 × 106 BM-MSCs obtained from CS-exposed or sham-exposed animal donors. Twenty-four hours after cell administration, animals were sacrificed and cells were visualised into lung structures by optical microscopy. BM-MSCs from 8 healthy GP and from 8 GP exposed to CS for 1 month were isolated from the femur, cultured in vitro and assessed for their proliferation, migration, senescence, differentiation potential and chemokine gene expression profile. RESULTS: CS-exposed animals showed greater BM-MSCs lung infiltration than sham-exposed animals regardless of route of administration. The majority of BM-MSCs localized in the alveolar septa. BM-MSCs obtained from CS-exposed animals showed lower ability to engraft and lower proliferation and migration. In vitro, BM-MSCs exposed to CS extract showed a significant reduction of proliferative, cellular differentiation and migratory potential and an increase in cellular senescence in a dose dependent manner. CONCLUSION: Short-term CS exposure induces BM-MSCs dysfunction. Such dysfunction was observed in vivo, affecting the cell homing and proliferation capabilities of BM-MSCs in lungs exposed to CS and in vitro altering the rate of proliferation, senescence, differentiation and migration capacity. Additionally, CS induced a reduction in CXCL9 gene expression in the BM from CS-exposed animals underpinning a potential mechanistic action of bone marrow dysfunction.


Assuntos
Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Fumar Cigarros/efeitos adversos , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/patologia , Fumaça/efeitos adversos , Animais , Células da Medula Óssea/efeitos dos fármacos , Movimento Celular/imunologia , Cobaias , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Modelos Animais
16.
Int J Cardiol ; 228: 238-243, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27865192

RESUMO

BACKGROUND: Endothelial dysfunction is key in the development of pulmonary hypertension (PH) and is associated with reduced number of circulating progenitor cells. Studies to date evaluating levels of circulating progenitor cells in PH have provided conflicting results. Current treatment of pulmonary arterial hypertension (PAH) and medical treatment of chronic thromboembolic pulmonary hypertension (CTEPH) targets endothelium dependent signalling pathways. The effect of PAH-targeted therapy on circulating progenitor cells has not been clearly established. OBJECTIVES: To investigate whether levels of circulating progenitor cells in treatment-naïve patients with PAH or CTEPH differ from healthy subjects and to assess the effect of PAH-targeted therapy on the circulating levels of these progenitors. METHODS: Thirty controls, 33 PAH and 11 CTEPH treatment-naïve patients were studied. Eighteen patients with PAH and 9 with CTEPH were re-evaluated 6-12months after starting PAH-targeted therapy. Levels of progenitors were measured by flow cytometry as CD45+CD34+ and CD45+CD34+CD133+ cells. RESULTS: Compared with controls, the number of circulating progenitor cells was reduced in PAH but not in CTEPH. After 6-12months of treatment, levels of circulating progenitors increased in PAH and remained unchanged in CTEPH. Patients with lower exercise tolerance presented lower levels of circulating progenitors. No other relation was found between levels of progenitors and clinical or hemodynamic parameters. CONCLUSIONS: Patients with PAH, but not those with CTEPH, present reduced levels of circulating progenitor cells. PAH-targeted therapy increases levels of progenitors in PAH but not in CTEPH, suggesting different involvement of progenitor cells in the pathobiology of these pulmonary hypertensive disorders.


Assuntos
Hipertensão Pulmonar/sangue , Embolia Pulmonar/sangue , Células-Tronco , Adulto , Idoso , Estudos de Casos e Controles , Contagem de Células , Doença Crônica , Estudos Transversais , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/terapia , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/fisiopatologia , Embolia Pulmonar/terapia
18.
PLoS One ; 11(7): e0159460, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27441378

RESUMO

OBJECTIVE: Previous studies have confirmed Slug as a key player in regulating phenotypic changes in several cell models, however, its role in smooth muscle cells (SMC) has never been assessed. The purpose of this study was to evaluate the expression of Slug during the phenotypic switch of SMC in vitro and throughout the development of vascular remodeling. METHODS AND RESULTS: Slug expression was decreased during both cell-to-cell contact and TGFß1 induced SMC differentiation. Tumor necrosis factor-α (TNFα), a known inductor of a proliferative/dedifferentiated SMC phenotype, induces the expression of Slug in SMC. Slug knockdown blocked TNFα-induced SMC phenotypic change and significantly reduced both SMC proliferation and migration, while its overexpression blocked the TGFß1-induced SMC differentiation and induced proliferation and migration. Genome-wide transcriptomic analysis showed that in SMC, Slug knockdown induced changes mainly in genes related to proliferation and migration, indicating that Slug controls these processes in SMC. Notably, Slug expression was significantly up-regulated in lungs of mice using a model of pulmonary hypertension-related vascular remodeling. Highly remodeled human pulmonary arteries also showed an increase of Slug expression compared to less remodeled arteries. CONCLUSIONS: Slug emerges as a key transcription factor driving SMC towards a proliferative phenotype. The increased Slug expression observed in vivo in highly remodeled arteries of mice and human suggests a role of Slug in the pathogenesis of pulmonary vascular diseases.


Assuntos
Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Remodelação Vascular , Animais , Desdiferenciação Celular/efeitos dos fármacos , Desdiferenciação Celular/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos Endogâmicos C57BL , Modelos Biológicos , Fenótipo , Artéria Pulmonar/patologia , Fatores de Transcrição da Família Snail/genética , Fator de Crescimento Transformador beta1/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/genética
19.
Basic Res Cardiol ; 111(4): 49, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27328822

RESUMO

Beta-3 adrenergic receptor (ß3AR) agonists have been shown to produce vasodilation and prevention of ventricular remodeling in different conditions. Given that these biological functions are critical in pulmonary hypertension (PH), we aimed to demonstrate a beneficial effect of ß3AR agonists in PH. An experimental study in pigs (n = 34) with chronic PH created by pulmonary vein banding was designed to evaluate the acute hemodynamic effect and the long-term effect of ß3AR agonists on hemodynamics, vascular remodeling and RV performance in chronic PH. Ex vivo human experiments were performed to explore the expression of ß3AR mRNA and the vasodilator response of ß3AR agonists in pulmonary arteries. Single intravenous administration of the ß3AR agonist BRL37344 produced a significant acute reduction in PVR, and two-weeks treatment with two different ß3AR selective agonists, intravenous BRL37344 or oral mirabegron, resulted in a significant reduction in PVR (median of -2.0 Wood units/m(2) for BRL37344 vs. +1.5 for vehicle, p = 0.04; and -1.8 Wood units/m(2) for mirabegron vs. +1.6 for vehicle, p = 0.002) associated with a significant improvement in magnetic resonance-measured RV performance. Histological markers of pulmonary vascular proliferation (p27 and Ki67) were significantly attenuated in ß3AR agonists-treated pigs. ß3AR was expressed in human pulmonary arteries and ß3AR agonists produced vasodilatation. ß3AR agonists produced a significant reduction in PVR and improved RV performance in experimental PH, emerging as a potential novel approach for treating patients with chronic PH.


Assuntos
Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Hipertensão Pulmonar/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Resistência Vascular/efeitos dos fármacos , Acetanilidas/farmacologia , Animais , Western Blotting , Modelos Animais de Doenças , Feminino , Humanos , Imuno-Histoquímica , Masculino , Nebivolol/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real , Suínos , Tiazóis/farmacologia , Remodelação Ventricular/efeitos dos fármacos
20.
Am J Physiol Lung Cell Mol Physiol ; 310(7): L583-92, 2016 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-26801565

RESUMO

Pulmonary vessel remodeling in chronic obstructive pulmonary disease (COPD) involves changes in smooth muscle cell proliferation, which are highly dependent on the coordinated interaction of angiogenic-related growth factors. The purpose of the study was to investigate, in isolated pulmonary arteries (PA) from patients with COPD, the gene expression of 46 genes known to be modulators of the angiogenic process and/or involved in smooth muscle cell proliferation and to relate it to vascular remodeling. PA segments were isolated from 29 patients and classified into tertiles, according to intimal thickness. After RNA extraction, the gene expression was assessed by RT-PCR using TaqMan low-density arrays. The univariate analysis only showed upregulation of angiopoietin-2 (ANGPT-2) in remodeled PA (P < 0.05). The immunohistochemical expression of ANGPT-2 correlated with intimal enlargement (r = 0.42, P < 0.05). However, a combination of 10 factors in a multivariate discriminant analysis model explained up to 96% of the classification of the arteries. A network analysis of 46 genes showed major decentralization. In this network, the metalloproteinase-2 (MMP-2) was shown to be the bridge between intimal enlargement and fibrogenic factors. In COPD patients, plasma levels of ANGPT-2 were higher in current smokers or those with pulmonary hypertension. We conclude that an imbalance in ANGPT-2, combined with related factors such as VEGF, ß-catenin, and MMP-2, may partially explain the structural derangements of the arterial wall. MMP-2 may act as a bridge channeling actions from the main fibrogenic factors.


Assuntos
Angiopoietina-2/genética , Artéria Pulmonar/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Transcriptoma , Idoso , Angiopoietina-2/metabolismo , Humanos , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Túnica Íntima/metabolismo , Remodelação Vascular
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