Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 11.361
Filtrar
1.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445357

RESUMO

The biological activities of interleukins, a group of circulating cytokines, are linked to the immuno-pathways involved in many diseases. Mounting evidence suggests that interleukin-1ß (IL-1ß) plays a significant role in the pathogenesis of various types of hypertension. In this review, we summarized recent findings linking IL-1ß to systemic arterial hypertension, pulmonary hypertension, and gestational hypertension. We also outlined the new progress in elucidating the potential mechanisms of IL-1ß in hypertension, focusing on it's regulation in inflammation, vascular smooth muscle cell function, and extracellular remodeling. In addition, we reviewed recent studies that highlight novel findings examining the function of non-coding RNAs in regulating the activity of IL-1ß and its associated proteins in the setting of hypertension. The information collected in this review provides new insights into understanding the pathogenesis of hypertension and could lead to the discovery of new anti-hypertensive therapies to combat this highly prevalent disease.


Assuntos
Hipertensão/etiologia , Interleucina-1beta/fisiologia , Animais , Matriz Extracelular/patologia , Matriz Extracelular/fisiologia , Feminino , Regulação da Expressão Gênica , Humanos , Hipertensão/patologia , Hipertensão/fisiopatologia , Hipertensão Induzida pela Gravidez/etiologia , Hipertensão Induzida pela Gravidez/patologia , Hipertensão Induzida pela Gravidez/fisiopatologia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Inflamação/complicações , Inflamação/fisiopatologia , Interleucina-1beta/genética , Músculo Liso Vascular/fisiopatologia , Gravidez , RNA não Traduzido/fisiologia , Remodelação Vascular/fisiologia
2.
Medicine (Baltimore) ; 100(27): e25915, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34232164

RESUMO

ABSTRACT: Early right ventricular dysfunction in patients with non-advanced idiopathic pulmonary fibrosis (IPF) has not been fully elucidated. Thus, we aimed to assess right ventricular functions in IPF patients and controls by speckle-tracking strain echocardiography at rest and peak exercise.We screened 116 IPF patients from February to August 2019 to include 20 patients with no history of oxygen therapy, peripheral saturation levels ≥92% at rest, Gender-Age-Physiology Index score ≤5, and modified Medical Research Council score ≤3. Additionally, we enrolled 10 matched controls. Transthoracic echocardiography images were acquired at rest and during a cardiopulmonary exercise test. We analyzed 2-dimensional echocardiographic parameters and right ventricular function using the global longitudinal strain assessed by the 2-dimensional speckle-tracking technique.In the control group, we found normal values of right ventricle longitudinal strain (RVLS) at rest and at peak exercise, the latter being much more negative (-23.6 ±â€Š2.2% and -26.8 ±â€Š3.1%, respectively; P < .001). By contrast, RVLS values in the IPF group increased from -21.1 ±â€Š3.8% at rest to -17.0 ±â€Š4.5% at peak exercise (P < .001). The exercise revealed a difference between the 2 groups as the mean RVLS values moved during peak exercise in opposite directions. Patients with IPF got worse, whereas control patients presented improved right ventricular contractility.Right ventricular dysfunction was unveiled by speckle-tracking echocardiography during exercise in non-advanced IPF patients. We suggest that this reflects an inadequate right ventricular-arterial coupling decreasing the right ventricular longitudinal contraction during exercise in these patients. This parameter may be useful as an early index of suspected pulmonary hypertension.


Assuntos
Terapia por Exercício/métodos , Exercício Físico/fisiologia , Ventrículos do Coração/fisiopatologia , Hipertensão Pulmonar/fisiopatologia , Fibrose Pulmonar Idiopática/fisiopatologia , Contração Miocárdica/fisiologia , Função Ventricular Direita/fisiologia , Idoso , Estudos Transversais , Ecocardiografia , Feminino , Ventrículos do Coração/diagnóstico por imagem , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/terapia , Fibrose Pulmonar Idiopática/complicações , Masculino
3.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067108

RESUMO

Pulmonary hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular failure and premature death. There are multiple clinical manifestations that can be grouped into five different types. Pulmonary artery remodeling is a common feature in pulmonary hypertension (PH) characterized by endothelial dysfunction and smooth muscle pulmonary artery cell proliferation. The current treatments for PH are limited to vasodilatory agents that do not stop the progression of the disease. Therefore, there is a need for new agents that inhibit pulmonary artery remodeling targeting the main genetic, molecular, and cellular processes involved in PH. Chronic inflammation contributes to pulmonary artery remodeling and PH, among other vascular disorders, and many inflammatory mediators signal through the JAK/STAT pathway. Recent evidence indicates that the JAK/STAT pathway is overactivated in the pulmonary arteries of patients with PH of different types. In addition, different profibrotic cytokines such as IL-6, IL-13, and IL-11 and growth factors such as PDGF, VEGF, and TGFß1 are activators of the JAK/STAT pathway and inducers of pulmonary remodeling, thus participating in the development of PH. The understanding of the participation and modulation of the JAK/STAT pathway in PH could be an attractive strategy for developing future treatments. There have been no studies to date focused on the JAK/STAT pathway and PH. In this review, we focus on the analysis of the expression and distribution of different JAK/STAT isoforms in the pulmonary arteries of patients with different types of PH. Furthermore, molecular canonical and noncanonical JAK/STAT pathway transactivation will be discussed in the context of vascular remodeling and PH. The consequences of JAK/STAT activation for endothelial cells and pulmonary artery smooth muscle cells' proliferation, migration, senescence, and transformation into mesenchymal/myofibroblast cells will be described and discussed, together with different promising drugs targeting the JAK/STAT pathway in vitro and in vivo.


Assuntos
Hipertensão Pulmonar/fisiopatologia , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Remodelação Vascular , Animais , Humanos , Modelos Biológicos
4.
Am J Physiol Heart Circ Physiol ; 321(1): H242-H252, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34085841

RESUMO

Disturbed balance between matrix metalloproteinases (MMPs) and their respective tissue inhibitors (TIMPs) is a well-recognized pathophysiological component of pulmonary arterial hypertension (PAH). Both classes of proteinases have been associated with clinical outcomes as well as with specific pathological features of ventricular dysfunction and pulmonary arterial remodeling. The purpose of this study was to evaluate the circulating levels of MMPs and TIMPs in children with PAH undergoing the same-day cardiac magnetic resonance imaging (MRI) and right heart catheterization. Children with PAH (n = 21) underwent a same-day catheterization, comprehensive cardiac MRI evaluation, and blood sample collection for proteomic analysis. Correlative analysis was performed between protein levels and 1) standard PAH indices from catheterization, 2) cardiac MRI hemodynamics, and 3) pulmonary arterial stiffness. MMP-8 was significantly associated with the right ventricular end-diastolic volume (R = 0.45, P = 0.04). MMP-9 levels were significantly associated with stroke volume (R = -0.49, P = 0.03) and pulmonary vascular resistance (R = 0.49, P = 0.03). MMP-9 was further associated with main pulmonary arterial stiffness evaluated by relative area change (R = -0.79, P < 0.01).TIMP-2 and TIMP-4 levels were further associated with the right pulmonary artery pulse wave velocity (R = 0.51, P = 0.03) and backward compression wave (R = 0.52, P = 0.02), respectively. MMPs and TIMPs warrant further clinically prognostic evaluation in conjunction with the conventional cardiac MRI hemodynamic indices.NEW & NOTEWORTHY Metalloproteinases have been associated with clinical outcomes in pulmonary hypertension and with specific pathological features of ventricular dysfunction and pulmonary arterial remodeling. In this study, we demonstrated that plasma circulating levels of metalloproteinases and their inhibitors are associated with standard cardiac MRI hemodynamic indices and with the markers of proximal pulmonary arterial stiffness. Particularly, MMP-9 and TIMP-2 were associated with several different markers of pulmonary arterial stiffness. These findings suggest the interplay between the extracellular matrix (ECM) remodeling and overall hemodynamic status in children with PAH might be assessed using the peripheral circulating MMP and TIMP levels.


Assuntos
Hipertensão Pulmonar/fisiopatologia , Metaloproteinases da Matriz/sangue , Inibidores Teciduais de Metaloproteinases/sangue , Rigidez Vascular/fisiologia , Função Ventricular/fisiologia , Adolescente , Pressão Arterial/fisiologia , Criança , Feminino , Hemodinâmica/fisiologia , Humanos , Hipertensão Pulmonar/sangue , Masculino , Artéria Pulmonar/fisiopatologia
5.
Am J Physiol Heart Circ Physiol ; 321(2): H318-H338, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34142886

RESUMO

Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by recurrent or unresolved pulmonary thromboemboli, leading to perfusion defects and increased arterial wave reflections. CTEPH treatment aims to reduce pulmonary arterial pressure and reestablish adequate lung perfusion, yet patients with distal lesions are inoperable by standard surgical intervention. Instead, these patients undergo balloon pulmonary angioplasty (BPA), a multisession, minimally invasive surgery that disrupts the thromboembolic material within the vessel lumen using a catheter balloon. However, there still lacks an integrative, holistic tool for identifying optimal target lesions for treatment. To address this insufficiency, we simulate CTEPH hemodynamics and BPA therapy using a multiscale fluid dynamics model. The large pulmonary arterial geometry is derived from a computed tomography (CT) image, whereas a fractal tree represents the small vessels. We model ring- and web-like lesions, common in CTEPH, and simulate normotensive conditions and four CTEPH disease scenarios; the latter includes both large artery lesions and vascular remodeling. BPA therapy is simulated by simultaneously reducing lesion severity in three locations. Our predictions mimic severe CTEPH, manifested by an increase in mean proximal pulmonary arterial pressure above 20 mmHg and prominent wave reflections. Both flow and pressure decrease in vessels distal to the lesions and increase in unobstructed vascular regions. We use the main pulmonary artery (MPA) pressure, a wave reflection index, and a measure of flow heterogeneity to select optimal target lesions for BPA. In summary, this study provides a multiscale, image-to-hemodynamics pipeline for BPA therapy planning for patients with inoperable CTEPH. NEW & NOTEWORTHY This article presents novel computational framework for predicting pulmonary hemodynamics in chronic thromboembolic pulmonary hypertension. The mathematical model is used to identify the optimal target lesions for balloon pulmonary angioplasty, combining simulated pulmonary artery pressure, wave intensity analysis, and a new quantitative metric of flow heterogeneity.


Assuntos
Hemodinâmica , Hipertensão Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Embolia Pulmonar/fisiopatologia , Angioplastia com Balão , Doença Crônica , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/terapia , Modelos Cardiovasculares , Modelos Teóricos , Artéria Pulmonar/diagnóstico por imagem , Embolia Pulmonar/complicações , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/terapia
6.
Am J Physiol Heart Circ Physiol ; 321(2): H382-H389, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34142888

RESUMO

Pulmonary hypertension (PH) is associated with structural remodeling of pulmonary arteries (PAs) because of excessive proliferation of fibroblasts, endothelial cells, and smooth muscle cells (SMCs). The peptide hormone angiotensin II (ANG II) contributes to pulmonary vascular remodeling, in part, through its ability to trigger extracellular signal-regulated kinase (ERK1/2) activation. Here, we demonstrate that the ERK1/2 phosphatase, dual-specificity phosphatase 5 (DUSP5), functions as a negative regulator of ANG II-mediated SMC proliferation and PH. In contrast to wild-type controls, Dusp5 null mice infused with ANG II developed PH and right ventricular (RV) hypertrophy. PH in Dusp5 null mice was associated with thickening of the medial layer of small PAs, suggesting an in vivo role for DUSP5 as a negative regulator of ANG II-dependent SMC proliferation. Consistent with this, overexpression of DUSP5 blocked ANG II-mediated proliferation of cultured human pulmonary artery SMCs (hPASMCs) derived from patients with idiopathic PH or from failed donor controls. Collectively, the data support a role for DUSP5 as a feedback inhibitor of ANG II-mediated ERK signaling and PASMC proliferation and suggest that disruption of this circuit leads to adverse cardiopulmonary remodeling.NEW & NOTEWORTHY Dual-specificity phosphatases (DUSPs) serve critical roles in the regulation of mitogen-activated protein kinases, but their functions in the cardiovascular system remain poorly defined. Here, we provide evidence that DUSP5, which resides in the nucleus and specifically dephosphorylates extracellular signal-regulated kinase (ERK1/2), blocks pulmonary vascular smooth muscle cell proliferation. In response to angiotensin II infusion, mice lacking DUSP5 develop pulmonary hypertension and right ventricular cardiac hypertrophy. These findings illustrate DUSP5-mediated suppression of ERK signaling in the lungs as a protective mechanism.


Assuntos
Proliferação de Células/genética , Fosfatases de Especificidade Dupla/genética , Ventrículos do Coração/metabolismo , Hipertensão Pulmonar/genética , Hipertrofia Ventricular Direita/genética , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/metabolismo , Remodelação Vascular/genética , Angiotensina II/farmacologia , Animais , Estudos de Casos e Controles , Células Cultivadas , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/induzido quimicamente , Hipertrofia Ventricular Direita/fisiopatologia , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Knockout , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Vasoconstritores/farmacologia
8.
Chest ; 159(4): e237-e241, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-34022025

RESUMO

CASE PRESENTATION: A 44-year-old man presented to the ED with acute massive hemoptysis and hypoxia. His history was notable for 1 year of progressively worsening shortness of breath at both rest and with exertion. He denied chest discomfort and endorsed near syncope while driving in recent months. He recently had been treated with antibiotics for two episodes of presumed pneumonia, based on right lower lobe opacification on chest radiography.


Assuntos
Dispneia/etiologia , Hemoptise/etiologia , Artéria Pulmonar/anormalidades , Malformações Vasculares/complicações , Adulto , Diagnóstico Diferencial , Dispneia/diagnóstico , Hemoptise/diagnóstico , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Masculino , Artéria Pulmonar/diagnóstico por imagem , Pressão Propulsora Pulmonar/fisiologia , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Malformações Vasculares/diagnóstico
9.
J Cardiothorac Surg ; 16(1): 127, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33971931

RESUMO

BACKGROUND: This study aimed to explore whether the mechanical stretching-induced expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in pulmonary veins occurred through the stretch-activated channel (SAC)/ mitogen-activated protein kinases (MAPKs) pathway. METHODS: Sixty male Sprague-Dawley rats were divided into three sham groups and seven model groups. A metal clip was placed on the ascending aorta in the model group to establish PH-LHD rat model. The sham group received a similar operation without ascending aorta clamped. On day 25, pulmonary vein was given mechanical stretching with 0 g, 2.0 g tension in two model groups and two sham groups. Another four model groups were given 2.0 g tension after MAPKs pathway inhibitors soaked. The last sham group and model group rats' pulmonary veins, pulmonary artery and lung tissues were obtained on day 35. Pulmonary vein, pulmonary artery and lung tissue were evaluated by echocardiography, HE staining, immunohistochemistry and western blotting respectively. RESULTS: On day 25, left heart weight, right ventricular pressure (35.339 cmH2O) and left atrial pressure (13.657 cmH2O) were increased in model group than those in sham group. Echocardiography showed left heart failure in the PH-LHD group (Interventrieular septum dimension 1.716 mm, left ventricular internal end diastolic dimension 4.888 mm, left ventricular posterior wall thickness in diastole 1.749 mm, ejection fraction 76.917%). But there was no difference in lung tissue between the sham group and PH-LHD group as showed by HE staining. Our results showed that the expression of IL-6 and TNF-α was highly expressed in PH-LHD rats' serum and pulmonary vein, which were further increased after 2.0 g tension was given and were decreased after SAC/MAPKs inhibitors treatment. Meanwhile, on day 25, immunohistochemistry analysis showed the expression of IL-6 and TNF-α was higher in the PH-LHD rats' pulmonary vein than that in pulmonary artery and lung tissue, and these expressions in pulmonary vein of PH-LHD group were also higher than that in sham group. However, on day 35, IL-6 and TNF-α were all increased in the pulmonary veins, arteries and lung tissues. Besides, our results uncovered that SAC/MAPKs pathway were upregulating in PH-LHD rats' pulmonary vein. CONCLUSION: In conclusion, pulmonary vein mechanical stretching exacerbated PH-LHD possibly through the SAC/MAPKs pathway and upregulating expression of IL-6 and TNF-α.


Assuntos
Hipertensão Pulmonar/etiologia , Interleucina-6/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Veias Pulmonares/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Remodelação Vascular/fisiologia , Disfunção Ventricular Esquerda/fisiopatologia , Animais , Biomarcadores/metabolismo , Fenômenos Biomecânicos , Western Blotting , Ecocardiografia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Imuno-Histoquímica , Masculino , Veias Pulmonares/diagnóstico por imagem , Veias Pulmonares/patologia , Veias Pulmonares/fisiopatologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Regulação para Cima
10.
Am J Med Sci ; 361(6): 731-735, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33947586

RESUMO

BACKGROUND: The relationship between the presence of pleural and pericardial effusion in reference to hemodynamic parameters remains unclear in ambulatory patients with pulmonary hypertension (PH). METHODS: Consecutive patients who underwent right catheterization (RHC) for the evaluation of pulmonary hypertension were enrolled. Point-of- care ultrasound was performed prior to the RHC to determine the presence of pleural effusion and pericardial effusion. We conducted a cross-sectional study to determine the association between presence of pericardial and pleural effusion with pulmonary hemodynamic variables. RESULTS: Twenty-five (78.1%) of 32 patients had evidence of PH by RHC. Mean pulmonary artery pressure of the population was 40.6 mmHg, and 68% (17/25) had WHO group I PH. Six (24.0%) of 25 PH patients had pleural effusions identified, of which 4 out of 6 (66.7%) had a pulmonary artery wedge pressure >15 mmHg. Eleven (44.0%) of the 25 PH patients were also found to have pericardial effusions, and most of those patients 10/11(90.9%) had an elevated right atrial pressure >10 mmHg. The presence of a pleural effusion was associated with a pulmonary artery wedge pressure >15 mmHg (p = 0.032) and the presence of a pericardial effusion was associated with a right atrial pressure >10 mmHg (p = 0.004). Detection of pleural effusion had a poor positive predictive value (67%) for the presence of pulmonary venous hypertension, whereas presence of a pericardial effusion was highly predictive (89%) of the presence of systemic venous hypertension. CONCLUSIONS: Systemic venous hypertension was associated with the presence of pericardial effusions, while pulmonary venous hypertension is associated with pleural effusion development in ambulatory patients with pulmonary hypertension.


Assuntos
Hemodinâmica/fisiologia , Hipertensão Pulmonar/diagnóstico por imagem , Derrame Pericárdico/diagnóstico por imagem , Derrame Pleural/diagnóstico por imagem , Ultrassonografia de Intervenção/métodos , Adulto , Idoso , Cateterismo Cardíaco/métodos , Estudos Transversais , Feminino , Humanos , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Derrame Pericárdico/epidemiologia , Derrame Pericárdico/fisiopatologia , Derrame Pleural/epidemiologia , Derrame Pleural/fisiopatologia , Testes Imediatos
11.
Int J Mol Sci ; 22(8)2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33917769

RESUMO

Chronic pulmonary hypertension (PH) is a fatal disease characterized by the persistent activation of pulmonary vascular cells that exhibit aberrant expression of genes including miRNAs. We and others reported that decreased levels of mature microRNA-124 (miR-124) plays an important role in modulating the activated phenotype of pulmonary vascular cells and HDAC inhibitors (HDACi) can restore the levels of mature miR-124 and reverse the persistently activated phenotype of PH vascular cells. In this study, we sought to determine the mechanisms contributing to reduced levels of miRNAs, as well as how HDACi restores the levels of reduced miRNA in PH vascular cells. We found that pulmonary artery fibroblasts isolated from IPAH patients (PH-Fibs) exhibit reduced levels of mature miR-124 and several other miRNAs including let-7i, miR-224, and miR-210, and that these reduced levels can be restored by HDACi. Using miR-124 expression in human PH-Fibs as a model, we determined that reduced miR-124 gene transcription, not decreased expression of miRNA processing genes, is responsible for reduced levels of mature miR-124 in human PH-Fibs. Using both DNase I Sensitivity and chromatin immunoprecipitation assays, we found that the miR-124-1 gene exhibits a more condensed chromatin structure in human PH-Fibs, compared to corresponding controls. HDACi relaxed miR-124-1 chromatin structure, evidenced by increased levels of the open chromatin mark H3K27Ac, but decreased levels of closed chromatin mark H3K27Me3. Most importantly, the delivery of histone acetyltransferase (HAT) via CRISPR-dCas9-HAT and guiding RNAs to the promoter of the miR-124-1 gene increased miR-124-1 gene transcription. Thus, our data indicate epigenetic events play important role in controlling miR-124 and likely other miRNA levels and epigenetic regulators such as HDACs appear to be promising therapeutic targets for chronic PH.


Assuntos
Suscetibilidade a Doenças , Regulação da Expressão Gênica , Hipertensão Pulmonar/etiologia , MicroRNAs/genética , Animais , Biomarcadores , Células Cultivadas , Cromatina/genética , Cromatina/metabolismo , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Sequências Reguladoras de Ácido Nucleico , Transcrição Genética
13.
Front Immunol ; 12: 640718, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868271

RESUMO

The recruitment and subsequent polarization of inflammatory monocytes/macrophages in the perivascular regions of pulmonary arteries is a key feature of pulmonary hypertension (PH). However, the mechanisms driving macrophage polarization within the adventitial microenvironment during PH progression remain unclear. We previously established that reciprocal interactions between fibroblasts and macrophages are essential in driving the activated phenotype of both cell types although the signals involved in these interactions remain undefined. We sought to test the hypothesis that adventitial fibroblasts produce a complex array of metabolites and proteins that coordinately direct metabolomic and transcriptomic re-programming of naïve macrophages to recapitulate the pathophysiologic phenotype observed in PH. Media conditioned by pulmonary artery adventitial fibroblasts isolated from pulmonary hypertensive (PH-CM) or age-matched control (CO-CM) calves were used to activate bone marrow derived macrophages. RNA-Seq and mass spectrometry-based metabolomics analyses were performed. Fibroblast conditioned medium from patients with idiopathic pulmonary arterial hypertension or controls were used to validate transcriptional findings. The microenvironment was targeted in vitro using a fibroblast-macrophage co-culture system and in vivo in a mouse model of hypoxia-induced PH. Both CO-CM and PH-CM actively, yet distinctly regulated macrophage transcriptomic and metabolomic profiles. Network integration revealed coordinated rewiring of pro-inflammatory and pro-remodeling gene regulation in concert with altered mitochondrial and intermediary metabolism in response to PH-CM. Pro-inflammation and metabolism are key regulators of macrophage phenotype in vitro, and are closely related to in vivo flow sorted lung interstitial/perivascular macrophages from hypoxic mice. Metabolic changes are accompanied by increased free NADH levels and increased expression of a metabolic sensor and transcriptional co-repressor, C-terminal binding protein 1 (CtBP1), a mechanism shared with adventitial PH-fibroblasts. Targeting the microenvironment created by both cell types with the CtBP1 inhibitor MTOB, inhibited macrophage pro-inflammatory and metabolic re-programming both in vitro and in vivo. In conclusion, coordinated transcriptional and metabolic reprogramming is a critical mechanism regulating macrophage polarization in response to the complex adventitial microenvironment in PH. Targeting the adventitial microenvironment can return activated macrophages toward quiescence and attenuate pathological remodeling that drives PH progression.


Assuntos
Microambiente Celular/fisiologia , Hipertensão Pulmonar/fisiopatologia , Ativação de Macrófagos/fisiologia , Macrófagos Alveolares/metabolismo , Animais , Bovinos , Células Cultivadas , Reprogramação Celular/efeitos dos fármacos , Reprogramação Celular/fisiologia , Técnicas de Cocultura , Meios de Cultivo Condicionados/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Hipertensão Pulmonar/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Transcriptoma
14.
J Comput Assist Tomogr ; 45(3): 415-420, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33797443

RESUMO

OBJECTIVES: The aim of this study was to determine the difference and correlation in pulmonary artery (PA) size when measured from the electrocardiogram (ECG)-gated computed tomography (CT) and non-ECG-gated CT. METHODS: In the retrospective study, 279 patients who underwent both ECG-gated CT and non-ECG-gated CT were enrolled. Maximum and minimum diameters of main pulmonary artery (MPA), right pulmonary artery (RPA), and ascending aorta (AAO) were measured, whereas mean diameters of MPA and RPA were obtained. The same PA size parameters were also measured on non-ECG-gated CT. RESULTS: There was a significant difference in maximum and minimum PA diameters between ECG-gated CT and non-ECG-gated CT, whereas mean PA diameters showed no statistically difference. The PA parameters showed a strong positive correlation between these 2 examinations. CONCLUSIONS: The PA size was different between ECG-gated CT and non-ECG-gated CT, whereas the PA size parameters on non-ECG-gated CT could be used to predict those with ECG-gated CT, which allow for confident prediction of pulmonary hypertension and guide further surgical intervention.


Assuntos
Técnicas de Imagem de Sincronização Cardíaca/métodos , Cardiopatias Congênitas/diagnóstico por imagem , Hipertensão Pulmonar/diagnóstico por imagem , Artéria Pulmonar/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Eletrocardiografia , Feminino , Cardiopatias Congênitas/patologia , Cardiopatias Congênitas/fisiopatologia , Humanos , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto Jovem
15.
Am J Physiol Regul Integr Comp Physiol ; 320(6): R800-R811, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33826424

RESUMO

Hypoxia at high altitude can constrain metabolism and performance and can elicit physiological adjustments that are deleterious to health and fitness. Hypoxic pulmonary hypertension is a particularly serious and maladaptive response to chronic hypoxia, which results from vasoconstriction and pathological remodeling of pulmonary arteries, and can lead to pulmonary edema and right ventricle hypertrophy. We investigated whether deer mice (Peromyscus maniculatus) native to high altitude have attenuated this maladaptive response to chronic hypoxia and whether evolved changes or hypoxia-induced plasticity in pulmonary vasculature might impact ventilation-perfusion (V-Q) matching in chronic hypoxia. Deer mouse populations from both high and low altitudes were born and raised to adulthood in captivity at sea level, and various aspects of lung function were measured before and after exposure to chronic hypoxia (12 kPa O2, simulating the O2 pressure at 4,300 m) for 6-8 wk. In lowlanders, chronic hypoxia increased right ventricle systolic pressure (RVSP) from 14 to 19 mmHg (P = 0.001), in association with thickening of smooth muscle in pulmonary arteries and right ventricle hypertrophy. Chronic hypoxia also impaired V-Q matching in lowlanders (measured at rest using SPECT-CT imaging), as reflected by increased log SD of the perfusion distribution (log SDQ) from 0.55 to 0.86 (P = 0.031). In highlanders, chronic hypoxia had attenuated effects on RVSP and no effects on smooth muscle thickness, right ventricle mass, or V-Q matching. Therefore, evolved changes in lung function help attenuate maladaptive plasticity and contribute to hypoxia tolerance in high-altitude deer mice.


Assuntos
Hipertensão Pulmonar/fisiopatologia , Hipóxia/fisiopatologia , Consumo de Oxigênio/fisiologia , Oxigênio/metabolismo , Peromyscus/metabolismo , Aclimatação/fisiologia , Animais , Hipertensão Pulmonar/metabolismo , Pulmão/fisiopatologia , Camundongos , Perfusão , Peromyscus/fisiologia
16.
Am J Physiol Regul Integr Comp Physiol ; 320(6): R835-R850, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33826428

RESUMO

Pulmonary hypertension (PH) is a serious disease with pulmonary arterial fibrotic remodeling and limited responsiveness to vasodilators. Our data suggest that mild acidosis induced by carbonic anhydrase inhibition could ameliorate PH, but the vascular mechanisms are unclear. We tested the hypothesis that carbonic anhydrase inhibition ameliorates PH by improving pulmonary vascular reactivity and relaxation mechanisms. Male Sprague-Dawley rats were either control normoxic (Nx), or injected with Sugen 5416 (20 mg/kg, sc) and subjected to hypoxia (9% O2) (Su + Hx), or Su + Hx treated with acetazolamide (ACTZ, 100 mg/kg/day, in drinking water). After measuring the hemodynamics, right ventricular hypertrophy was assessed by Fulton's Index; vascular function was measured in pulmonary artery, aorta, and mesenteric arteries; and pulmonary arteriolar remodeling was assessed in lung sections. Right ventricular systolic pressure and Fulton's Index were increased in Su + Hx and reduced in Su + Hx + ACTZ rats. Pulmonary artery contraction to KCl and phenylephrine were reduced in Su + Hx and improved in Su + Hx + ACTZ. Acetylcholine (ACh)-induced relaxation and nitrate/nitrite production were reduced in pulmonary artery of Su + Hx and improved in Su + Hx + ACTZ. ACh relaxation was blocked by nitric oxide (NO) synthase and guanylate cyclase inhibitors, supporting a role of NO-cGMP. Sodium nitroprusside (SNP)-induced relaxation was reduced in pulmonary artery of Su + Hx, and ACTZ enhanced relaxation to SNP. Contraction/relaxation were not different in aorta or mesenteric arteries of all groups. Pulmonary arterioles showed wall thickening in Su + Hx that was ameliorated in Su + Hx + ACTZ. Thus, amelioration of pulmonary hemodynamics during carbonic anhydrase inhibition involves improved pulmonary artery reactivity and NO-mediated relaxation and may enhance responsiveness to vasodilator therapies in PH.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Hipertensão Pulmonar/fisiopatologia , Músculo Liso Vascular/fisiopatologia , Artéria Pulmonar/fisiopatologia , Animais , Hipóxia/fisiopatologia , Masculino , Artérias Mesentéricas/fisiopatologia , Óxido Nítrico/metabolismo , Óxido Nítrico/farmacologia , Ratos Sprague-Dawley , Vasodilatação/efeitos dos fármacos
17.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805714

RESUMO

Trifluoperazine (TFP), an antipsychotic drug approved by the Food and Drug Administration, has been show to exhibit anti-cancer effects. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive obliteration of small pulmonary arteries (PAs) due to exaggerated proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). However, the therapeutic potential of TFP for correcting the cancer-like phenotype of PAH-PASMCs and improving PAH in animal models remains unknown. PASMCs isolated from PAH patients were exposed to different concentrations of TFP before assessments of cell proliferation and apoptosis. The in vivo therapeutic potential of TFP was tested in two preclinical models with established PAH, namely the monocrotaline and sugen/hypoxia-induced rat models. Assessments of hemodynamics by right heart catheterization and histopathology were conducted. TFP showed strong anti-survival and anti-proliferative effects on cultured PAH-PASMCs. Exposure to TFP was associated with downregulation of AKT activity and nuclear translocation of forkhead box protein O3 (FOXO3). In both preclinical models, TFP significantly lowered the right ventricular systolic pressure and total pulmonary resistance and improved cardiac function. Consistently, TFP reduced the medial wall thickness of distal PAs. Overall, our data indicate that TFP could have beneficial effects in PAH and support the view that seeking new uses for old drugs may represent a fruitful approach.


Assuntos
Fármacos Cardiovasculares/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Hipóxia/prevenção & controle , Miócitos de Músculo Liso/efeitos dos fármacos , Trifluoperazina/farmacologia , Animais , Antipsicóticos/farmacologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Feminino , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Hemodinâmica/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/fisiopatologia , Hipóxia/induzido quimicamente , Hipóxia/genética , Hipóxia/fisiopatologia , Indóis/administração & dosagem , Monocrotalina/administração & dosagem , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/citologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Pirróis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Survivina/genética , Survivina/metabolismo
18.
Proc Natl Acad Sci U S A ; 118(11)2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33836561

RESUMO

Interferonopathies, interferon (IFN)-α/ß therapy, and caveolin-1 (CAV1) loss-of-function have all been associated with pulmonary arterial hypertension (PAH). Here, CAV1-silenced primary human pulmonary artery endothelial cells (PAECs) were proliferative and hypermigratory, with reduced cytoskeletal stress fibers. Signal transducers and activators of transcription (STAT) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) were both constitutively activated in these cells, resulting in a type I IFN-biased inflammatory signature. Cav1 -/- mice that spontaneously develop pulmonary hypertension were found to have STAT1 and AKT activation in lung homogenates and increased circulating levels of CXCL10, a hallmark of IFN-mediated inflammation. PAH patients with CAV1 mutations also had elevated serum CXCL10 levels and their fibroblasts mirrored phenotypic and molecular features of CAV1-deficient PAECs. Moreover, immunofluorescence staining revealed endothelial CAV1 loss and STAT1 activation in the pulmonary arterioles of patients with idiopathic PAH, suggesting that this paradigm might not be limited to rare CAV1 frameshift mutations. While blocking JAK/STAT or AKT rescued aspects of CAV1 loss, only AKT inhibitors suppressed activation of both signaling pathways simultaneously. Silencing endothelial nitric oxide synthase (NOS3) prevented STAT1 and AKT activation induced by CAV1 loss, implicating CAV1/NOS3 uncoupling and NOS3 dysregulation in the inflammatory phenotype. Exogenous IFN reduced CAV1 expression, activated STAT1 and AKT, and altered the cytoskeleton of PAECs, implicating these mechanisms in PAH associated with autoimmune and autoinflammatory diseases, as well as IFN therapy. CAV1 insufficiency elicits an IFN inflammatory response that results in a dysfunctional endothelial cell phenotype and targeting this pathway may reduce pathologic vascular remodeling in PAH.


Assuntos
Caveolina 1/genética , Endotélio Vascular/metabolismo , Hipertensão Pulmonar/metabolismo , Interferon Tipo I/metabolismo , Animais , Células Cultivadas , Endotélio Vascular/enzimologia , Endotélio Vascular/fisiopatologia , Inativação Gênica , Humanos , Hipertensão Pulmonar/fisiopatologia , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais
19.
Biomed Res Int ; 2021: 8870615, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33728346

RESUMO

The aim of this study was to evaluate the effects of a 6-month combined aerobic and strength exercise training program on functional and psychological aspects and health-related quality of life in patients with PH and to evaluate its longer-term impact. In total, 22 stable patients (mean age 53.9 ± 13.8, 13 female) with pulmonary hypertension of World Health Organization (WHO) class I-III participated in a nine-month study. They were randomly assigned into two groups: Group A participated in a 6-month combined aerobic and strength exercise training program, whereas Group B remained untrained. All patients underwent physical and psychological assessment at baseline and at month 6 (after completing the exercise program) and physical assessment after 9 months (3 months posttraining). After the 6-month exercise training program, patients of Group A significantly improved their physical (6MWD, STS 10 rep, STS 20 rep, TUG, lower limb strength, cardiopulmonary exercise time, METs, peak VO2, VCO2, and VE/VCO2 slope) and psychological aspects (SF-36, STAI, and BDI). Between the two groups, differences were observed at the 6MWD (95% CI: 36.2-64.6, η 2 = 0.72), STS 10 rep (95% CI: 6.6-2.2, η 2 = 0.4), STS 20 rep (95% CI: 10.8-2.4, η 2 = 0.34), lower limb strength (95% CI: 7.2-3.6, η 2 = 0.38), cardiopulmonary exercise time (95% CI: 0.1-3.3, η 2 = 0.2), and VCO2 (95% CI: 0.1-0.5, η 2 = 0.2). Additionally, psychological changes were noted at SF-36, PCS (95% CI: 3.6-14.8, η 2 = 0.35), MCS (95% CI: 1.3-16.1, η 2 = 0.22), TCS (95% CI: 1.3-16.1, η 2 = 0.22), and STAI (95% CI: 1.8-28.2, η 2 = 0.18). The favorable results of exercise were maintained at the 3-month posttraining follow-up assessment. No exercise-induced complications were observed throughout the study. In conclusion, a long-term exercise training program is a safe and effective intervention to improve functional status, psychological aspects, and health-related quality of life in patients with PH.


Assuntos
Terapia por Exercício , Exercício Físico , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/terapia , Qualidade de Vida , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...