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1.
Biomed Res Int ; 2021: 6634417, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33959659

RESUMO

Background: MicroRNAs (miRNAs) play an important role in the pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH). However, the potential correlation between miRNA expression and the severity of CTEPH remains unclear. Our previous study indicated that miRNAs hsa-let-7b-3p, hsa-miR-17-5p, hsa-miR-106b-5p, hsa-miR-3202, hsa-miR-665, and hsa-miR-93-5p are closely involved in CTEPH. This study assessed the associations between the expression levels of these miRNAs and clinical parameters in CTEPH patients. Methods: A total of eight CTEPH patients and eight healthy adults as a reference group were included, and clinical data including total protein (TP), albumin (Alb), lactate dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBDH), uric acid (UA), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were collected. Right heart catheterization was conducted to obtain hemodynamic data including cardiac index (CI). The expression levels of let-7b-3p, miR-17-5p, miR-106b-5p, miR-3202, miR-665, and miR-93-5p were measured by quantitative real-time PCR (qPCR). Correlation analysis was applied to estimate the associations between miRNA expression levels and clinical parameters in CTEPH patients. Results: Serum TP and Alb levels were decreased, while LDH, HBDH, and UA levels were increased in CTEPH patients compared with the reference group (P < 0.05). miR-3202 and miR-665 were upregulated, whereas let-7b-3p, miR-17-5p, miR-106b-5p, and miR-93-5p were downregulated in CTEPH patients relative to the reference group (P < 0.05). miR-93-5p expression was positively correlated with NT-proBNP level and negatively correlated with CI (P < 0.05). Moreover, let-7b-3p tended to be positively correlated with mean pulmonary arterial pressure. Conclusions: miR-93-5p expression was associated with the severity of CTEPH and could act as a potential predictor of high-risk CTEPH.


Assuntos
Hipertensão Pulmonar , MicroRNAs , Tromboembolia , Idoso , Biomarcadores/análise , Biomarcadores/metabolismo , Feminino , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Masculino , MicroRNAs/sangue , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Tromboembolia/sangue , Tromboembolia/genética , Tromboembolia/metabolismo
2.
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
3.
Nat Commun ; 12(1): 1720, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741934

RESUMO

Pulmonary arterial hypertension is a progressive fatal disease that is characterized by pathological pulmonary artery remodeling, in which endothelial cell dysfunction is critically involved. We herein describe a previously unknown role of endothelial angiocrine in pulmonary hypertension. By searching for genes highly expressed in lung microvascular endothelial cells, we identify inhibin-ß-A as an angiocrine factor produced by pulmonary capillaries. We find that excess production of inhibin-ß-A by endothelial cells impairs the endothelial function in an autocrine manner by functioning as activin-A. Mechanistically, activin-A induces bone morphogenetic protein receptor type 2 internalization and targeting to lysosomes for degradation, resulting in the signal deficiency in endothelial cells. Of note, endothelial cells isolated from the lung of patients with idiopathic pulmonary arterial hypertension show higher inhibin-ß-A expression and produce more activin-A compared to endothelial cells isolated from the lung of normal control subjects. When endothelial activin-A-bone morphogenetic protein receptor type 2 link is overdriven in mice, hypoxia-induced pulmonary hypertension was exacerbated, whereas conditional knockout of inhibin-ß-A in endothelial cells prevents the progression of pulmonary hypertension. These data collectively indicate a critical role for the dysregulated endothelial activin-A-bone morphogenetic protein receptor type 2 link in the progression of pulmonary hypertension, and thus endothelial inhibin-ß-A/activin-A might be a potential pharmacotherapeutic target for the treatment of pulmonary arterial hypertension.


Assuntos
Ativinas/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Hipertensão Pulmonar/metabolismo , Animais , Apoptose , Modelos Animais de Doenças , Endocitose , Células Endoteliais/metabolismo , Técnicas de Inativação de Genes , Humanos , Hipertensão Pulmonar/patologia , Hipóxia , Subunidades beta de Inibinas , Inibinas , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Hipertensão Arterial Pulmonar , Remodelação Vascular
5.
Am J Physiol Heart Circ Physiol ; 320(4): H1526-H1534, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33577434

RESUMO

Use of electronic cigarettes is rapidly increasing among youth and young adults, but little is known regarding the long-term cardiopulmonary health impacts of these nicotine-containing devices. Our group has previously demonstrated that chronic, inhaled nicotine induces pulmonary hypertension (PH) and right ventricular (RV) remodeling in mice. These changes were associated with upregulated RV angiotensin-converting enzyme (ACE). Angiotensin II receptor blockers (ARBs) have been shown to reverse cigarette smoking-induced PH in rats. ACE inhibitor and ARB use in a large retrospective cohort of patients with PH is associated with improved survival. Here, we utilized losartan (an ARB specific for angiotensin II type 1 receptor) to further explore nicotine-induced PH. Male C57BL/6 mice received nicotine vapor for 12 h/day, and exposure was assessed using serum cotinine to achieve levels comparable to human smokers or electronic cigarette users. Mice were exposed to nicotine for 8 wk and a subset was treated with losartan via an osmotic minipump. Cardiac function was assessed using echocardiography and catheterization. Although nicotine exposure increased angiotensin II in the RV and lung, this finding was nonsignificant. Chronic, inhaled nicotine significantly increased RV systolic pressure and RV free wall thickness versus air control. These parameters were significantly lower in mice receiving both nicotine and losartan. Nicotine significantly increased RV internal diameter, with no differences seen between the nicotine and nicotine-losartan group. Neither nicotine nor losartan affected left ventricular structure or function. These findings provide the first evidence that antagonism of the angiotensin II type 1 receptor can ameliorate chronic, inhaled nicotine-induced PH and RV remodeling.NEW & NOTEWORTHY Chronic, inhaled nicotine causes pulmonary hypertension and right ventricular remodeling in mice. Treatment with losartan, an angiotensin II type 1 receptor antagonist, ameliorates nicotine-induced pulmonary hypertension and right ventricular remodeling. This novel finding provides preclinical evidence for the use of renin-angiotensin system-based therapies in the treatment of pulmonary hypertension, particularly in patients with a history of tobacco-product use.


Assuntos
Pressão Arterial , Vapor do Cigarro Eletrônico , Hipertensão Pulmonar/metabolismo , Hipertrofia Ventricular Direita/metabolismo , Nicotina , Artéria Pulmonar/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Função Ventricular Direita , Remodelação Ventricular , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Modelos Animais de Doenças , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/prevenção & controle , Hipertrofia Ventricular Direita/induzido quimicamente , Hipertrofia Ventricular Direita/patologia , Hipertrofia Ventricular Direita/prevenção & controle , Exposição por Inalação , Losartan/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Transdução de Sinais , Fatores de Tempo , Função Ventricular Direita/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
6.
Brief Bioinform ; 22(2): 1451-1465, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33611340

RESUMO

This study aimed to identify significant gene expression profiles of the human lung epithelial cells caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. We performed a comparative genomic analysis to show genomic observations between SARS-CoV and SARS-CoV-2. A phylogenetic tree has been carried for genomic analysis that confirmed the genomic variance between SARS-CoV and SARS-CoV-2. Transcriptomic analyses have been performed for SARS-CoV-2 infection responses and pulmonary arterial hypertension (PAH) patients' lungs as a number of patients have been identified who faced PAH after being diagnosed with coronavirus disease 2019 (COVID-19). Gene expression profiling showed significant expression levels for SARS-CoV-2 infection responses to human lung epithelial cells and PAH lungs as well. Differentially expressed genes identification and integration showed concordant genes (SAA2, S100A9, S100A8, SAA1, S100A12 and EDN1) for both SARS-CoV-2 and PAH samples, including S100A9 and S100A8 genes that showed significant interaction in the protein-protein interactions network. Extensive analyses of gene ontology and signaling pathways identification provided evidence of inflammatory responses regarding SARS-CoV-2 infections. The altered signaling and ontology pathways that have emerged from this research may influence the development of effective drugs, especially for the people with preexisting conditions. Identification of regulatory biomolecules revealed the presence of active promoter gene of SARS-CoV-2 in Transferrin-micro Ribonucleic acid (TF-miRNA) co-regulatory network. Predictive drug analyses provided concordant drug compounds that are associated with SARS-CoV-2 infection responses and PAH lung samples, and these compounds showed significant immune response against the RNA viruses like SARS-CoV-2, which is beneficial in therapeutic development in the COVID-19 pandemic.


Assuntos
/complicações , Hipertensão Pulmonar/complicações , /isolamento & purificação , Algoritmos , Biomarcadores/metabolismo , /virologia , Ontologia Genética , Humanos , Hipertensão Pulmonar/metabolismo , Armazenamento e Recuperação da Informação , MicroRNAs/metabolismo , Filogenia , Mapas de Interação de Proteínas , Fatores de Transcrição/metabolismo
7.
Mol Biol Rep ; 48(1): 975-981, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33394231

RESUMO

Calcium-sensing receptor (CaSR) is widely involved in the cell proliferation, differentiation, migration, adhesion and apoptosis, which can affect the vascular remodeling in the humanbody. The main ligand of CaSR is extracellular Ca2+. CaSR has the physiological significance in Ca2+ homeostasis. Pulmonary vascular remodeling is one of the main histopathological changes of pulmonary hypertension (PH). The abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) results in the pulmonary vascular remodeling. CaSR is an important regulator of [Ca2+]i. [Ca2+]i is the main cause of the excessive pulmonary vascular remodeling in patients with PH. In this review, it was conclued that the structure of CaSR was prone to explore the devolopment or the treatment of PH. It was found that the regulation of CaSR with some miRNA could inhibit the proliferation of PASMCs, and that CaSR could affect the occurrence of autophagy in PH. Therefore, CaSR would become a new therapeutic target to PH.


Assuntos
Adamantano/análogos & derivados , Bloqueadores dos Canais de Cálcio/uso terapêutico , Cálcio/metabolismo , Hipertensão Pulmonar/genética , Quinoxalinas/uso terapêutico , Receptores de Detecção de Cálcio/genética , Remodelação Vascular/efeitos dos fármacos , Adamantano/uso terapêutico , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Regulação da Expressão Gênica , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Receptores de Detecção de Cálcio/antagonistas & inibidores , Receptores de Detecção de Cálcio/metabolismo , Transdução de Sinais , Remodelação Vascular/genética
8.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498172

RESUMO

In the heart, connexins form gap junctions, hemichannels, and are also present within mitochondria, with connexin 43 (Cx43) being the most prominent connexin in the ventricles. Whereas the role of Cx43 is well established for the healthy and diseased left ventricle, less is known about the importance of Cx43 for the development of right ventricular (RV) dysfunction. The present article focusses on the importance of Cx43 for the developing heart. Furthermore, we discuss the expression and localization of Cx43 in the diseased RV, i.e., in the tetralogy of Fallot and in pulmonary hypertension, in which the RV is affected, and RV hypertrophy and failure occur. We will also introduce other Cx molecules that are expressed in RV and surrounding tissues and have been reported to be involved in RV pathophysiology. Finally, we highlight therapeutic strategies aiming to improve RV function in pulmonary hypertension that are associated with alterations of Cx43 expression and function.


Assuntos
Conexina 43/metabolismo , Hipertensão Pulmonar/metabolismo , Tetralogia de Fallot/metabolismo , Função Ventricular , Animais , Conexina 43/genética , Ventrículos do Coração/metabolismo , Humanos , Hipertensão Pulmonar/genética , Tetralogia de Fallot/genética
9.
Am J Physiol Lung Cell Mol Physiol ; 320(4): L508-L521, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33502933

RESUMO

We have previously reported that several patients with idiopathic pulmonary hypertension (PH) had different types of G6PD deficiency. However, the role of G6PD in PH is multifactorial because G6PD is involved in controlling oxidative stress, metabolic switch, and red blood cell fragility. To delineate the contribution of G6PD to PH pathogenesis, we utilized a mouse line with decreased expression of G6PD (10% from wild-type level). We confirmed that mice with G6PD deficiency develop spontaneous pulmonary hypertension with pulmonary artery and right heart remodeling. G6PD deficiency resulted in increased free hemoglobin and activation of the p38 pathway, which we recently reported induces the development of PH in the sugen/hypoxia model via endothelial barrier dysfunction. Metabolomics analysis of G6PD deficient mice indicates the switch to alternative metabolic fluxes that feed into the pentose phosphate pathway (PPP), resulting in the upregulation of oxidative stress, fatty acid pathway, and reduction in pyruvate production. Thus, G6PD deficiency did not reduce PPP flux that is important for proliferation but activated collateral pathways at the cost of increased oxidative stress. Indeed, we found the upregulation of myo-inositol oxidase, reduction in GSH/GSSG ratio, and increased nitration in the lungs of G6PD-deficient mice. Increased oxidative stress also results in the activation of PI3K, ERK1/2, and AMPK that contribute to the proliferation of pulmonary vasculature. Therefore, G6PD deficiency has a multimodal effect, including hemolysis, metabolic reprogramming, and oxidative stress leading to the PH phenotype in mice.


Assuntos
Deficiência de Glucosefosfato Desidrogenase/complicações , Glucosefosfato Desidrogenase/metabolismo , Hipertensão Pulmonar/patologia , Metaboloma , Estresse Oxidativo , Artéria Pulmonar/patologia , Animais , Estudos de Casos e Controles , Feminino , Hemólise , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Knockout , Oxirredução , Artéria Pulmonar/metabolismo
10.
Am J Physiol Heart Circ Physiol ; 320(3): H980-H990, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33416457

RESUMO

Perinatal hypoxia induces permanent structural and functional changes in the lung and its pulmonary circulation that are associated with the development of pulmonary hypertension (PH) in later life. The mechanistic target of the rapamycin (mTOR) pathway is vital for fetal lung development and is implicated in hypoxia-associated PH, yet its involvement in the developmental programming of PH remains unclear. Pregnant C57/BL6 dams were placed in hyperbaric (760 mmHg) or hypobaric chambers during gestation (505 mmHg, day 15 through postnatal day 4) or from weaning through adulthood (420 mmHg, postnatal day 21 through 8 wk). Pulmonary hemodynamics and right ventricular systolic pressure (RVSP) were measured at 8 wk. mTOR pathway proteins were assessed in fetal (day 18.5) and adult lung (8 wk). Perinatal hypoxia induced PH during adulthood, even in the absence of a sustained secondary hypoxic exposure, as indicated by reduced pulmonary artery acceleration time (PAAT) and peak flow velocity through the pulmonary valve, as well as greater RVSP, right ventricular (RV) wall thickness, and RV/left ventricular (LV) weight. Such effects were independent of increased blood viscosity. In fetal lung homogenates, hypoxia reduced the expression of critical downstream mTOR targets, most prominently total and phosphorylated translation repressor protein (4EBP1), as well as vascular endothelial growth factor, a central regulator of angiogenesis in the fetal lung. In contrast, adult offspring of hypoxic dams tended to have elevated p4EBP1 compared with controls. Our data suggest that inhibition of mTORC1 activity in the fetal lung as a result of gestational hypoxia may interrupt pulmonary vascular development and thereby contribute to the developmental programming of PH.NEW & NOTEWORTHY We describe the first study to evaluate a role for the mTOR pathway in the developmental programming of pulmonary hypertension. Our findings suggest that gestational hypoxia impairs mTORC1 activation in the fetal lung and may impede pulmonary vascular development, setting the stage for pulmonary vascular disease in later life.


Assuntos
Hipóxia Fetal/complicações , Hipertensão Pulmonar/etiologia , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Neovascularização Fisiológica , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Modelos Animais de Doenças , Feminino , Hipóxia Fetal/metabolismo , Hipóxia Fetal/fisiopatologia , Idade Gestacional , Hemodinâmica , Oxigenação Hiperbárica , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Camundongos Endogâmicos C57BL , Fosforilação , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Circulação Pulmonar , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Função Ventricular Direita , Pressão Ventricular
11.
Mol Med Rep ; 23(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33313943

RESUMO

Pulmonary hypertension (PH) is a life­threatening disease that often involves vascular remodeling. Although pulmonary arterial smooth muscle cells (PASMCs) are the primary participants in vascular remodeling, their biological role is not entirely clear. The present study analyzed the role of enhancer of zeste homolog 2 (EZH2) in vascular remodeling of PH by investigating the behavior of PASMCs. The expression levels of EZH2 in PASMCs in chronic thromboembolic pulmonary hypertension (CTEPH), a type of PH, were detected. The role of EZH2 in PASMC migration was investigated by wound­healing assay following overexpression and knockdown. Functional enrichment analysis of the whole­genome expression profiles of PASMCs with EZH2 overexpression was performed using an mRNA Human Gene Expression Microarray. Quantitative (q)PCR was performed to confirm the results of the microarray. EZH2 expression levels increased in CTEPH cell models. The overexpression of EZH2 enhanced PASMC migration compared with control conditions. Functional enrichment analysis of the differentially expressed genes following EZH2 overexpression indicated a strong link between EZH2 and the immune inflammatory response and oxidoreductase activity in PASMCs. mRNA expression levels of superoxide dismutase 3 were verified by qPCR. The results suggested that EZH2 was involved in the migration of PASMCs in PH, and may serve as a potential target for the treatment of PH.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/biossíntese , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Músculo Liso Vascular/metabolismo , Artéria Pulmonar/metabolismo , Linhagem Celular , Movimento Celular/genética , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Ontologia Genética , Humanos , Hipertensão Pulmonar/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , NADPH Oxidase 1/metabolismo , Oxirredutases/metabolismo , Superóxido Dismutase/metabolismo , Análise Serial de Tecidos , Transcriptoma , Remodelação Vascular/genética
12.
PLoS One ; 15(9): e0235824, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881898

RESUMO

Pulmonary hypertension due to left heart disease (PH-LHD) is a momentous pulmonary hypertension disease, and left heart disease is the most familiar cause. Mechanical stretching may be a crucial cause of vascular remodeling. While, the underlining mechanism of mechanical stretching-induced in remodeling of pulmonary vein in the early stage of PH-LHD has not been completely elucidated. In our study, the PH-LHD model rats were successfully constructed. After 25 days, doppler echocardiography and hemodynamic examination were performed. In addition, after treatment, the levels of matrix metalloproteinase-9 (MMP-9) and transforming growth factor-ß1 (TGF-ß1) were determined by ELISA, immunohistochemistry and western blot assays in the pulmonary veins. Moreover, the pathological change of pulmonary tissues was evaluated by H&E staining. Our results uncovered that left ventricular insufficiency and interventricular septal shift could be observed in PH-LHD model rats, and the right ventricular systolic pressure (RVSP) and mean left atrial pressure (mLAP) were also elevated in PH-LHD model rats. Meanwhile, we found that MMP-9 and TGF-ß1 could be highly expressed in PH-LHD model rats. Besides, we revealed that stretch-activated channel (SAC)/mitogen-activated protein kinases (MAPKs) signaling pathway could be involved in the upregulations of MMP-9 and TGF-ß1 mediated by mechanical stretching in pulmonary vein. Therefore, current research revealed that mechanical stretching induced the increasing expressions of MMP-9 and TGF-ß1 in pulmonary vein, which could be mediated by activation of SAC/MAPKs signaling pathway in the early stage of PH-LHD.


Assuntos
Hipertensão Pulmonar/fisiopatologia , Sistema de Sinalização das MAP Quinases , Metaloproteinase 9 da Matriz/metabolismo , Veias Pulmonares/fisiopatologia , Fator de Crescimento Transformador beta1/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Ativação Enzimática , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Masculino , Veias Pulmonares/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse Mecânico , Remodelação Vascular , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/metabolismo
13.
Hypertension ; 76(3): 651-661, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32783758

RESUMO

Discovery of ACE2 (angiotensin-converting enzyme 2) revealed that the renin-angiotensin system has 2 counterbalancing arms. ACE2 is a major player in the protective arm, highly expressed in lungs and gut with the ability to mitigate cardiopulmonary diseases such as inflammatory lung disease. ACE2 also exhibits activities involving gut microbiome, nutrition, and as a chaperone stabilizing the neutral amino acid transporter, B0AT1, in gut. But the current interest in ACE2 arises because it is the cell surface receptor for the novel coronavirus, severe acute respiratory syndrome coronavirus-2, to infect host cells, similar to severe acute respiratory syndrome coronavirus-2. This suggests that ACE2 be considered harmful, however, because of its important other roles, it is paradoxically a potential therapeutic target for cardiopulmonary diseases, including coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2. This review describes the discovery of ACE2, its physiological functions, and its place in the renin-angiotensin system. It illustrates new analyses of the structure of ACE2 that provides better understanding of its actions particularly in lung and gut, shedding of ACE2 by ADAM17 (a disintegrin and metallopeptidase domain 17 protein), and role of TMPRSS2 (transmembrane serine proteases 2) in severe acute respiratory syndrome coronavirus-2 entry into host cells. Cardiopulmonary diseases are associated with decreased ACE2 activity and the mitigation by increasing ACE2 activity along with its therapeutic relevance are addressed. Finally, the potential use of ACE2 as a treatment target in COVID-19, despite its role to allow viral entry into host cells, is suggested.


Assuntos
Infecções por Coronavirus , Hipertensão Pulmonar , Pandemias , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral , Betacoronavirus/fisiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Gerenciamento Clínico , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/virologia , Pneumonia Viral/metabolismo , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Sistema Renina-Angiotensina/fisiologia
14.
Am J Physiol Lung Cell Mol Physiol ; 319(4): L627-L640, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32726132

RESUMO

Vitamin D (VitD) receptor regulates the expression of several genes involved in signaling pathways affected in pulmonary hypertension (PH). VitD deficiency is highly prevalent in PH, and low levels are associated with poor prognosis. We investigated if VitD deficiency may predispose to or exacerbate PH. Male Wistar rats were fed with a standard or a VitD-free diet for 5 wk. Next, rats were further divided into controls or PH, which was induced by a single dose of Su-5416 (20 mg/kg) and exposure to hypoxia (10% O2) for 2 wk. VitD deficiency had no effect on pulmonary pressure in normoxic rats, indicating that, by itself, it does not trigger PH. However, it induced several moderate but significant changes characteristic of PH in the pulmonary arteries, such as increased muscularization, endothelial dysfunction, increased survivin, and reduced bone morphogenetic protein (Bmp) 4, Bmp6, DNA damage-inducible transcript 4, and K+ two-pore domain channel subfamily K member 3 (Kcnk3) expression. Myocytes isolated from pulmonary arteries from VitD-deficient rats had a reduced whole voltage-dependent potassium current density and acid-sensitive (TASK-like) potassium currents. In rats with PH induced by Su-5416 plus hypoxia, VitD-free diet induced a modest increase in pulmonary pressure, worsened endothelial function, increased the hyperreactivity to serotonin, arterial muscularization, decreased total and TASK-1 potassium currents, and further depolarized the pulmonary artery smooth muscle cell membrane. In human pulmonary artery smooth muscle cells from controls and patients with PH, the active form of VitD calcitriol significantly increased KCNK3 mRNA expression. Altogether, these data strongly suggest that the deficit in VitD induces pulmonary vascular dysfunction.


Assuntos
Hipertensão Pulmonar/metabolismo , Músculo Liso Vascular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Deficiência de Vitamina D/metabolismo , Animais , Humanos , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Potenciais da Membrana/fisiologia , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/metabolismo , Ratos Wistar , Vitamina D/metabolismo
15.
Am J Respir Cell Mol Biol ; 63(4): 510-518, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32609558

RESUMO

Optimal oxygen saturation as measured by pulse oximetry (SpO2) in neonatal lung injury, such as meconium aspiration syndrome (MAS) and persistent pulmonary hypertension of newborn (PPHN), is not known. Our goal was to determine the SpO2 range in lambs with MAS and PPHN that results in the highest brain oxygen delivery (bDO2) and pulmonary blood flow (Qp) and the lowest pulmonary vascular resistance and oxidative stress. Meconium was instilled into endotracheal tubes in 25 near-term gestation lambs, and the umbilical cord was occluded to induce asphyxia and gasping, causing MAS and PPHN. Lambs were randomized into four groups and ventilated for 6 hours with fixed fraction of inspired oxygen (FiO2) = 1.0 irrespective of SpO2, and three groups had FiO2 titrated to keep preductal SpO2 between 85% and 89%, 90% and 94%, and 95% and 99%, respectively. Tissues were collected to measure nitric oxide synthase activity, 3-nitrotyrosine, and 8-isoprostanes. Throughout the 6-hour exposure period, lambs in the 95-99% SpO2 target group had the highest Qp, lowest pulmonary vascular resistance, and highest bDO2 but were exposed to higher FiO2 (0.5 ± 0.21 vs. 0.29 ± 0.17) with higher lung 3-nitrotyrosine (0.67 [interquartile range (IQR), 0.43-0.73] ng/mcg protein vs. 0.1 [IQR, 0.09-0.2] ng/mcg protein) and lower lung nitric oxide synthase activity (196 [IQR, 192-201] mMol nitrite/mg protein vs. 270 [IQR, 227-280] mMol nitrite/mg protein) compared with the 90-94% target group. Brain 3-nitrotyrosine was lower in the 85-89% target group, and brain/lung 8-isoprostane levels were not significantly different. In term lambs with MAS and PPHN, Qp and bDO2 through the first 6 hours are higher with target SpO2 in the 95-99% range. However, the 90-94% target range is associated with significantly lower FiO2 and lung oxidative stress. Clinical trials comparing the 90-94% versus the 95-99% SpO2 target range in term infants with PPHN are warranted.


Assuntos
Hipertensão Pulmonar/metabolismo , Pulmão/metabolismo , Síndrome de Aspiração de Mecônio/metabolismo , Oxigênio/metabolismo , Animais , Animais Recém-Nascidos , Dinoprosta/análogos & derivados , Dinoprosta/farmacologia , Feminino , Hipertensão Pulmonar/tratamento farmacológico , Pulmão/efeitos dos fármacos , Masculino , Síndrome de Aspiração de Mecônio/tratamento farmacológico , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oximetria/métodos , Síndrome da Persistência do Padrão de Circulação Fetal/tratamento farmacológico , Síndrome da Persistência do Padrão de Circulação Fetal/metabolismo , Gravidez , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Ovinos/metabolismo , Tirosina/análogos & derivados , Tirosina/farmacologia , Resistência Vascular/efeitos dos fármacos
16.
Nat Commun ; 11(1): 3527, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32669538

RESUMO

Ca2+ signaling in pulmonary arterial smooth muscle cells (PASMCs) plays an important role in pulmonary hypertension (PH). However, the underlying specific ion channel mechanisms remain largely unknown. Here, we report ryanodine receptor (RyR) channel activity and Ca2+ release both are increased, and association of RyR2 by FK506 binding protein 12.6 (FKBP12.6) is decreased in PASMCs from mice with chronic hypoxia (CH)-induced PH. Smooth muscle cell (SMC)-specific RyR2 knockout (KO) or Rieske iron-sulfur protein (RISP) knockdown inhibits the altered Ca2+ signaling, increased nuclear factor (NF)-κB/cyclin D1 activation and cell proliferation, and CH-induced PH in mice. FKBP12.6 KO or FK506 treatment enhances CH-induced PH, while S107 (a specific stabilizer of RyR2/FKBP12.6 complex) produces an opposite effect. In conclusion, CH causes RISP-dependent ROS generation and FKBP12.6/RyR2 dissociation, leading to PH. RISP inhibition, RyR2/FKBP12.6 complex stabilization and Ca2+ release blockade may be potentially beneficial for the treatment of PH.


Assuntos
Ciclina D1/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Hipertensão Pulmonar/metabolismo , NF-kappa B/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Animais , Sinalização do Cálcio , Proliferação de Células , Citosol/metabolismo , Humanos , Hipóxia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Miócitos de Músculo Liso/metabolismo , Oxigênio/metabolismo , Artéria Pulmonar/patologia , Espécies Reativas de Oxigênio/metabolismo , Transtornos Respiratórios/metabolismo , Transdução de Sinais
17.
Am J Physiol Lung Cell Mol Physiol ; 319(2): L360-L368, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32692577

RESUMO

Hypobaric hypoxia poses stress to sojourners traveling to high-altitude. A cascade of physiological changes occurs to cope with or adapt to hypobaric hypoxia. However, an insufficient physiological response to the hypoxic condition resulting from imbalanced vascular homeostasis pathways results in high-altitude pulmonary edema (HAPE). The present study aims to identify the implication of miRNAs associating with HAPE and adaptation. We analyzed the expression of 1,113 miRNAs in HAPE-patients (HAPE-p), HAPE-free controls (HAPE-f), and highland natives (HLs). Based on miRNA profiling and in silico analyses, miR-124-3p emerged relevantly. We observed a significant overexpression of miR-124-3p in HAPE-p. In silico analyses revealed a direct interaction of miR-124-3p with vascular homeostasis and hypoxia-associated genes NOS3 (endothelial nitric oxide synthase), Apelin, and ETS1 (V-Ets avian erythroblastosis virus E2 oncogene homolog 1). Moreover, the transcript and biolevel expression of these genes were significantly decreased in HAPE-p when compared with HAPE-f or HLs. Our in vitro analysis in human umbilical vein endothelial cells demonstrated a significant knockdown of these genes both at transcript and protein levels following miR-124-3p overexpression. Conclusively, our results showed that miR-124-3p might play a plausible role in HAPE pathophysiology by inhibiting the expression of NOS3, Apelin, and ETS1.


Assuntos
Doença da Altitude/sangue , Doença da Altitude/metabolismo , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/metabolismo , Hipóxia/sangue , Hipóxia/metabolismo , MicroRNAs/sangue , Edema Pulmonar/sangue , Edema Pulmonar/metabolismo , Adaptação Fisiológica/fisiologia , Adulto , Altitude , Apelina/metabolismo , Linhagem Celular , Feminino , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Proteína Proto-Oncogênica c-ets-1/metabolismo , Adulto Jovem
18.
Am J Physiol Lung Cell Mol Physiol ; 319(3): L422-L434, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32692581

RESUMO

The family of resistin-like molecules (RELMs) consists of four members in rodents (RELMα/FIZZ1/HIMF, RELMß/FIZZ2, Resistin/FIZZ3, and RELMγ/FIZZ4) and two members in humans (Resistin and RELMß), all of which exhibit inflammation-regulating, chemokine, and growth factor properties. The importance of these cytokines in many aspects of physiology and pathophysiology, especially in cardiothoracic diseases, is rapidly evolving in the literature. In this review article, we attempt to summarize the contribution of RELM signaling to the initiation and progression of lung diseases, such as pulmonary hypertension, asthma/allergic airway inflammation, chronic obstructive pulmonary disease, fibrosis, cancers, infection, and other acute lung injuries. The potential of RELMs to be used as biomarkers or risk predictors of these diseases also will be discussed. Better understanding of RELM signaling in the pathogenesis of pulmonary diseases may offer novel targets or approaches for the development of therapeutics to treat or prevent a variety of inflammation, tissue remodeling, and fibrosis-related disorders in respiratory, cardiovascular, and other systems.


Assuntos
Hipertensão Pulmonar/metabolismo , Resistina/metabolismo , Animais , Humanos , Inflamação/metabolismo , Transdução de Sinais/fisiologia
19.
Artigo em Inglês | MEDLINE | ID: mdl-32673988

RESUMO

Pulmonary hypertension (PH) is a progressive and life-threating lung disorder characterized by elevated pulmonary artery pressure and vascular remodeling. PH is classified into five groups, and one of the most common and lethal forms, PH Group-III is defined as PH due to lung diseases and/or hypoxia. Due to the lack of studies in this group, PH-specific drug therapies including prostacyclin (PGI2) analogues have not been approved or recommended for use in these patients. PGI2 is synthesized by the PGI2 synthase (PGIS) enzyme, and its production is determined by measuring its stable metabolite, 6-keto-PGF1α. An impaired PGI2 pathway has been observed in PH animal models and in PH Group-I patients; however, there are contradictory results. The aim of this study is to determine whether PH Group-III is associated with altered expression of PGIS and production of PGI2 in humans. To explore this hypothesis, we measured PGIS expression (by western blot) and PGI2 production (by ELISA) in a large variety of preparations from the pulmonary circulation including human pulmonary artery, pulmonary vein, distal lung tissue, pulmonary artery smooth muscle cells (hPASMC), and bronchi in PH Group-III (n = 35) and control patients (n = 32). Our results showed decreased PGIS expression and/or 6-keto-PGF1α levels in human pulmonary artery, hPASMC, and distal lung tissue derived from PH Group-III patients. Moreover, the production of 6-keto-PGF1α from hPASMC positively correlated with PGIS expression and was inversely correlated with mean pulmonary artery pressure. On the other hand, PH Group-III pulmonary veins and bronchi did not show altered PGI2 production compared to controls. The deficit in PGIS expression and/or PGI2 production observed in pulmonary artery and distal lung tissue in PH Group-III patients may have important implications in the pathogenesis and treatment of PH Group-III.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Epoprostenol/metabolismo , Hipertensão Pulmonar/metabolismo , Oxirredutases Intramoleculares/metabolismo , Artéria Pulmonar/metabolismo , Brônquios/enzimologia , Brônquios/metabolismo , Hipóxia Celular/fisiologia , Células Cultivadas , Dinoprosta/metabolismo , Regulação para Baixo , Feminino , Humanos , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/fisiopatologia , Pulmão/enzimologia , Pulmão/metabolismo , Masculino , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/metabolismo , Artéria Pulmonar/enzimologia , Veias Pulmonares/enzimologia , Veias Pulmonares/metabolismo
20.
Life Sci ; 257: 117919, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32585247

RESUMO

AIM: This study is undertaken to investigate the role and molecular mechanisms of miR-18a-5p in regulating pulmonary arterial hypertension (PAH) pathogenesis. METHODS: Gene expression and protein levels were determined by qRT-PCR and western blot, respectively; Cell counting kti-8 and Transwell migration assays were used to determine the biological functions of miR-18a-5p in pulmonary arterial smooth muscle cells (PASMCs); bioinformatics analysis, luciferase reporter assays were used to elucidate the mechanisms of miR-18a-5p. RESULTS: MiR-18a-5p was up-regulated in the clinical samples from PAH patients. PASMCs treated with hypoxia exhibited enhanced proliferative ability and upregulated miR-18a-5p expression. Knockdown of miR-18a-5p attenuated hypoxia-induced hyper-proliferation and enhanced migratory potential of PASMCs; while miR-18a-5p overexpression promoted PASMC proliferation and migration. Further mechanistic studies showed that Notch2 was a direct target of miR-18a-5p and was repressed by miR-18a-5p overexpression. The rescue studies indicated that Notch2 overexpression counteracted the enhanced proliferation and migration induced by miR-18a-5p mimics in PASMCs. Similarly, Notch2 overexpression also block the effects caused by hypoxia in PASMCs. Moreover, Notch2 expression was down-regulated in the PAH patients and was negatively correlated with miR-18a-5p expression. In vivo animal studies further revealed the up-regulation of miR-18a-5p and the down-regulation of Notch2 in the PAH rats. CONCLUSIONS: Collectively, this study identified the up-regulated miR-18a-5p in the PAH patients; our data suggest that miR-18a-5p contributes to the enhanced proliferation and migration of PASMCs via repressing Notch2 expression.


Assuntos
MicroRNAs/genética , Hipertensão Arterial Pulmonar/genética , Receptor Notch2/metabolismo , Animais , Apoptose/fisiologia , Hipóxia Celular/fisiologia , Movimento Celular/genética , Proliferação de Células/genética , Células Cultivadas , China , Hipertensão Pulmonar Primária Familiar/patologia , Feminino , Humanos , Hipertensão Pulmonar/metabolismo , Hipóxia/fisiopatologia , Masculino , MicroRNAs/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Ratos , Receptor Notch2/genética , Transdução de Sinais
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