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1.
Cell Prolif ; 53(2): e12742, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31943454

RESUMO

OBJECTIVES: Hypoxia is an important risk factor for pulmonary arterial remodelling in pulmonary arterial hypertension (PAH), and the Janus kinase 2 (JAK2) is believed to be involved in this process. In the present report, we aimed to investigate the role of JAK2 in vascular smooth muscle cells during the course of PAH. METHODS: Smooth muscle cell (SMC)-specific Jak2 deficient mice and their littermate controls were subjected to normobaric normoxic or hypoxic (10% O2 ) challenges for 28 days to monitor the development of PAH, respectively. To further elucidate the potential mechanisms whereby JAK2 influences pulmonary vascular remodelling, a selective JAK2 inhibitor was applied to pre-treat human pulmonary arterial smooth muscle cells (HPASMCs) for 1 hour followed by 24-hour hypoxic exposure. RESULTS: Mice with hypoxia-induced PAH were characterized by the altered JAK2/STAT3 activity in pulmonary artery smooth muscle cells. Therefore, induction of Jak2 deficiency in SMCs protected mice from hypoxia-induced increase of right ventricular systolic pressure (RVSP), right ventricular hypertrophy and pulmonary vascular remodelling. Particularly, loss of Jak2 significantly attenuated chronic hypoxia-induced PASMC proliferation in the lungs. Similarly, blockade of JAK2 by its inhibitor, TG-101348, suppressed hypoxia-induced human PASMC proliferation. Upon hypoxia-induced activation, JAK2 phosphorylated signal transducer and activator of transcription 3 (STAT3), which then bound to the CCNA2 promoter to transcribe cyclin A2 expression, thereby promoting PASMC proliferation. CONCLUSIONS: Our studies support that JAK2 could be a culprit contributing to the pulmonary vascular remodelling, and therefore, it could be a viable target for prevention and treatment of PAH in clinical settings.


Assuntos
Proliferação de Células/fisiologia , Hipóxia/metabolismo , Janus Quinase 2/antagonistas & inibidores , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipóxia/patologia , Janus Quinase 2/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Inibidores de Proteínas Quinases/farmacologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/patologia , Artéria Pulmonar/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/fisiologia
2.
Int Heart J ; 60(6): 1430-1434, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31735783

RESUMO

Pulmonary arterial hypertension is a fatal disease caused by pulmonary arterial vasoconstriction and organic stenosis due to the proliferation of pulmonary smooth muscle cells and endothelial cells. Endothelial dysfunction, including impaired nitric oxide (NO) bioavailability, plays a crucial role in the pathogenesis of pulmonary hypertension, and endothelial nitric oxide synthase (eNOS) is an important modulator of pulmonary vasodilatation. Although senescence marker protein (SMP) 30 is known as an anti-aging protein, the role of SMP30 in pulmonary vessels is still unclear. In this study, we examined the role of SMP30 in pulmonary vasculature using SMP30-deficient mice.We used female SMP30-deficient mice and wild-type littermate (WT) mice at the age of 12 to 18 weeks. The WT and SMP30-deficient mice were exposed to normoxia or hypoxia (10% oxygen for 4 weeks). In normoxia, the right ventricular systolic pressure (RVSP) was not different between the WT and SMP30-deficient mice, but in hypoxia, the RVSP was significantly higher in the SMP30-deficient mice compared to the WT mice (P < 0.05). The hypoxia-induced increases in right ventricular hypertrophy and medial smooth muscle area of the pulmonary artery were comparable between the WT and the SMP30-deficient mice. Western blotting showed that eNOS phosphorylation in lung tissue was reduced in the SMP30-deficient mice compared to the WT mice in normoxia. However, in hypoxic conditions, eNOS phosphorylation was reduced in both the WT and SMP30-deficient mice with no differences in Akt phosphorylation.Our study demonstrated that SMP30 is involved in the development of hypoxia-induced pulmonary hypertension by impairment of eNOS activity.


Assuntos
Proteínas de Ligação ao Cálcio/fisiologia , Hipertensão Pulmonar/etiologia , Hipóxia/complicações , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo III/metabolismo
3.
Zhonghua Nei Ke Za Zhi ; 58(10): 770-776, 2019 Oct 01.
Artigo em Chinês | MEDLINE | ID: mdl-31594176

RESUMO

Objective: To observe the levels of serum reactive oxygen species (ROS) and hydrogen sulfide(H(2)S) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD), and nicotinamide adenine dinucleotide phosphate-reduced (NADPH) oxidase 4 (NOX4) and cystathionine-γ-lyase (CSE) in lung tissue of patients with stable chronic obstructive pulmonary disease (COPD). Methods: (1) A total of 60 patients with AECOPD admitted to the Department of Respiratory Medicine at Ningxia Hui People's Hospital from November 2015 to December 2016 were recruited. According to the results of pulmonary function and echocardiography, the participants were divided into AECOPD-related pulmonary hypertension (PH) group(A) and AECOPD non-PH group (B).Other 30 healthy subjects were selected as the control group (C).Serum ROS and H(2)S of group A, B and C were detected by enzyme-linked immunosorbent assay (ELISA).(2)The lung tissues of patients undergoing lobectomy for lung cancer from November 2012 to April 2017 were collected, who were divided into COPD-related PH group (D), COPD non-PH group (E) and negative control (F). The expression of NOX4 and CSE protein in lung tissue was detected by immunohistochemistry and the thickness of pulmonary arteriole wall was measured. Results: (1)The serum ROS level in group A was higher than group B and C which were (613.52±69.66)IU/ml,(565.76±71.33)IU/ml, (294.63±60.39)IU/ml, respectively with that in group B higher than that in group C (P<0.05). Serum H(2)S level in group A was lower than group B and C, with that in group B lower than group C [(18.59±5.50) nmol/ml, (20.49±4.97) nmol/ml, (38.03±4.43) nmol/ml, respectively P<0.05]. ROS level was positively correlated with pulmonary systolic pressure (PASP) (r=0.59, P<0.05), H(2)S level was negatively correlated with PASP(r=-0.62, P<0.05).(2)The lung tissue expression of NOX4 in group D was higher than group E and F (P<0.05), which were 0.08±0.01,0.06±0.01,0.03±0.01, respectively,while the level of NOX4 in group E was higher than group F (P<0.05). The expression of CSE between group D, E and F were all significantly different (P<0.05),which were 0.03±0.01, 0.07±0.02,0.12±0.02, respectively.(3)Smooth muscle thickness of pulmonary arterioles as a percentage of vascular diameter (WT%) between group D, E and F was all different(P<0.05), which were (40.58±6.63)%,(36.87±5.60)%,(31.27±6.24)%, respectively; so was smooth muscle area of pulmonary arterioles as a percentage of total vascular area(WA%) with (32.33±6.27)%, (30.20±5.28)%, (25.20±4.31)%, respectively (P<0.05). (4)The expression of NOX4 was positively correlated with WT% and WA%, r was 0.81 and 0.66, respectively (P<0.05). The expression of CSE was negatively correlated with WT% and WA%, r was -0.55 and -0.39 respectively (P<0.05). Conclusions: NOX4/ROS and CSE/H(2)S signaling pathways may play an important role in the pathogenesis of COPD related PH.


Assuntos
Cistationina gama-Liase/metabolismo , Cistationina/metabolismo , Sulfeto de Hidrogênio/sangue , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , NADPH Oxidase 4/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Espécies Reativas de Oxigênio/sangue , Estudos de Casos e Controles , Humanos , Hipertensão Pulmonar/sangue , Oxirredutases , Doença Pulmonar Obstrutiva Crônica/sangue
4.
Nutr Metab Cardiovasc Dis ; 29(12): 1418-1428, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31653519

RESUMO

BACKGROUND AND AIMS: Intrauterine growth restriction (IUGR) is a state of slower fetal growth usually followed by a catch-up growth. Postnatal catch-up growth in IUGR models increases the incidence of pulmonary arterial hypertension in adulthood. Here, we hypothesize that the adverse pulmonary vascular consequences of IUGR may be improved by slowing down postnatal growth velocity. Meanwhile, cognitive function was also studied. METHODS AND RESULTS: We established an IUGR rat model by restricting maternal food throughout gestation. After birth, pups were fed a regular or restricted diet during lactation by changing litter size. Thus, there were three experimental groups according to the dam/offspring diet: C/C (gold standard), IUGR with catch-up growth (R/C) and IUGR with delayed growth (R/D). In adulthood (14 weeks of age), we assessed pulmonary vascular development by hemodynamic measurement and immunohistochemistry. Our results showed that adult R/C offspring developed an elevated mean pulmonary arterial pressure (mPAP) and pulmonary arteriolar remodeling accompanied with decreased eNOS mRNA and protein expressions compared to C/C or R/D offspring. This suggested that delayed postnatal growth improved pulmonary circulation compared to postnatal catch-up growth. Conversely, adult R/D offspring performed poorly in cognition. Behavior test and electrophysiology results exhibited a reduced synaptic plasticity. Furthermore, decreased mRNA expression levels of the memory-related gene zif268 and transcription factor recruitment factor p300 in the hippocampus region were also observed in R/D group. CONCLUSION: These findings indicate that delayed postnatal growth results in cognitive impairment, but it reverses elevations in mPAP induced by postnatal catch-up growth following IUGR.


Assuntos
Comportamento Animal , Encéfalo/crescimento & desenvolvimento , Restrição Calórica/efeitos adversos , Cognição , Disfunção Cognitiva/etiologia , Retardo do Crescimento Fetal/dietoterapia , Hipertensão Pulmonar/prevenção & controle , Artéria Pulmonar/crescimento & desenvolvimento , Fatores Etários , Fenômenos Fisiológicos da Nutrição Animal , Animais , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Retardo do Crescimento Fetal/psicologia , Hemodinâmica , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Masculino , Plasticidade Neuronal , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Artéria Pulmonar/metabolismo , Ratos Sprague-Dawley , Remodelação Vascular , Ganho de Peso
5.
Life Sci ; 237: 116769, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31422096

RESUMO

Hypoxic pulmonary hypertension (HPH) is a serious and potentially devastating disorder of the pulmonary circulation with complicated mechanisms. Long non-coding RNA (lncRNA) has been revealed to participate in HPH development. This study aimed to explore how lncRNA Tug1 affected the pulmonary vascular remodeling in HPH. A mouse model of HPH and a pulmonary artery smooth muscle cell (PASMC) model of HPH (HPH-PASMCs) were established, where the expression of lncRNA Tug1 was determined. Then, the interaction among lncRNA Tug1, miR-374c, and Foxc1 was assessed. Finally, in order to determine the effects of lncRNA Tug1 on PASMC activities and pulmonary vascular remodeling after HPH, the expression of lncRNA Tug1 was silenced in HPH-PASMCs and HPH mice, with the proliferation, apoptosis, and migration of PASMCs as well as blood pressure in mice measured, respectively. The obtained data revealed that lncRNA Tug1 was highly expressed in HPH mice and HPH-PASMCs. In addition, lncRNA Tug1 up-regulated the expression of Foxc1 by binding to miR-374c. Notably, silencing of lncRNA Tug1 inhibited the proliferation and migration, but promoted the apoptosis of PASMCs. Moreover, lncRNA Tug1 silencing was observed to attenuate the pulmonary vascular remodeling in HPH mice through the Foxc1-mediated NOTCH signaling pathway. Taken conjointly, silencing of lncRNA Tug1 down-regulated the Foxc1 expression by binding to miR-374c, thereby inhibiting the proliferation and migration, while promoting apoptosis of PASMCs to impede pulmonary vascular remodeling in HPH via the Notch signaling pathway. This study provided novel therapeutic insights for treating HPH.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Hipertensão Pulmonar/patologia , Hipóxia/fisiopatologia , MicroRNAs/genética , Músculo Liso Vascular/patologia , RNA Longo não Codificante/genética , Remodelação Vascular , Animais , Apoptose , Proliferação de Células , Células Cultivadas , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Artéria Pulmonar , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais
6.
Med Sci Monit ; 25: 5738-5746, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31373336

RESUMO

BACKGROUND miR-214-3p has been found to inhibit proliferation and migration in cancer cells. The objective of this study was to determine whether ARHGEF12 is involved in miR-214-3p-mediated suppression of proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). MATERIAL AND METHODS PASMCs were cultured under normoxia or hypoxia. miR-214-3p mimics or inhibitors were transiently transfected into PASMCs. Proliferation, apoptosis, and migration of PASMCs were evaluated using MTT assay, flow cytometry, and Boyden chamber apparatus. Western blot analysis was used to examine expression of Rho guanine nucleotide exchange factor 12 (ARHGEF12), c-fos, c-jun, and caspase-3. Luciferase reporter assay was used to test the direct regulation of miR-214-3p on the 3'-untranslated region (UTR) of ARHGEF12. RESULTS miR-214-3p was significantly upregulated in hypoxia-treated PASMCs. Knockdown of miR-214-3p significantly attenuated hypoxia-induced proliferation and migration in PASMCs and promoted apoptosis, whereas this effect was aggravated by overexpression of miR-214-3p. In addition, dual-luciferase reporter assay demonstrated that ARHGEF12 is a direct target gene of miR-214-3p. The protein levels of ARHGEF12 were downregulated after knockdown of miR-214-3p in PASMCs. Rescue experiment results indicated that decreased proliferation of PASMCs resulted from knockdown of miR-214-3p were partially reversed by silencing of ARHGEF12 by siRNA. Furthermore, knockdown of miR-214-3p reduced expression of c-jun and c-fos, but increased expression of caspase-3 in PASMCs under hypoxia. CONCLUSIONS In conclusion, these results indicate that miR-214-3p acts as a novel regulator of hypoxia-induced proliferation and migration by directly targeting ARHGEF12 and dysregulating c-jun and c-fos in PASMCs, and may be a potential therapeutic target for treating pulmonary hypertension.


Assuntos
Hipóxia Celular/fisiologia , MicroRNAs/metabolismo , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/metabolismo , Animais , Apoptose/fisiologia , Hipóxia Celular/genética , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , MicroRNAs/genética , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Cultura Primária de Células , Artéria Pulmonar/citologia , Ratos , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo
7.
Int J Mol Sci ; 20(17)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443549

RESUMO

Individuals ascending rapidly to altitudes >2500 m may develop symptoms of acute mountain sickness (AMS) within a few hours of arrival and/or high-altitude pulmonary edema (HAPE), which occurs typically during the first three days after reaching altitudes above 3000-3500 m. Both diseases have distinct pathologies, but both present with a pronounced decrease in oxygen saturation of hemoglobin in arterial blood (SO2). This raises the question of mechanisms impairing the diffusion of oxygen (O2) across the alveolar wall and whether the higher degree of hypoxemia is in causal relationship with developing the respective symptoms. In an attempt to answer these questions this article will review factors affecting alveolar gas diffusion, such as alveolar ventilation, the alveolar-to-arterial O2-gradient, and balance between filtration of fluid into the alveolar space and its clearance, and relate them to the respective disease. The resultant analysis reveals that in both AMS and HAPE the main pathophysiologic mechanisms are activated before aggravated decrease in SO2 occurs, indicating that impaired alveolar epithelial function and the resultant diffusion limitation for oxygen may rather be a consequence, not the primary cause, of these altitude-related illnesses.


Assuntos
Doença da Altitude/etiologia , Doença da Altitude/metabolismo , Altitude , Oxigênio/metabolismo , Alvéolos Pulmonares/metabolismo , Doença Aguda , Doença da Altitude/diagnóstico , Doença da Altitude/fisiopatologia , Animais , Difusão , Suscetibilidade a Doenças , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Hipóxia/complicações , Alvéolos Pulmonares/fisiopatologia , Vasoconstrição
9.
PLoS One ; 14(7): e0214697, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31339889

RESUMO

Neointimal lesion and medial wall thickness of pulmonary arteries (PAs) are common pathological findings in pulmonary arterial hypertension (PAH). Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling contribute to intimal and medial vascular remodeling in PAH. Nintedanib is a tyrosine kinase inhibitor whose targets include PDGF and FGF receptors. Although the beneficial effects of nintedanib were demonstrated for human idiopathic pulmonary fibrosis, its efficacy for PAH is still unclear. Thus, we hypothesized that nintedanib is a novel treatment for PAH to inhibit the progression of vascular remodeling in PAs. We evaluated the inhibitory effects of nintedanib both in endothelial mesenchymal transition (EndMT)-induced human pulmonary microvascular endothelial cells (HPMVECs) and human pulmonary arterial smooth muscle cells (HPASMCs) stimulated by growth factors. We also tested the effect of chronic nintedanib administration on a PAH rat model induced by Sugen5416 (a VEGF receptor inhibitor) combined with chronic hypoxia. Nintedanib was administered from weeks 3 to 5 after Sugen5416 injection, and we evaluated pulmonary hemodynamics and PAs pathology. Nintedanib attenuated the expression of mesenchymal markers in EndMT-induced HPMVECs and HPASMCs proliferation. Phosphorylation of PDGF and FGF receptors was augmented in both intimal and medial lesions of PAs. Nintedanib blocked these phosphorylation, improved hemodynamics and reduced vascular remodeling involving neointimal lesions and medial wall thickening in PAs. Additionally, expressions Twist1, transcription factors associated with EndMT, in lung tissue was significantly reduced by nintedanib. These results suggest that nintedanib may be a novel treatment for PAH with anti-vascular remodeling effects.


Assuntos
Proliferação de Células/efeitos dos fármacos , Células Endoteliais , Hipertensão Pulmonar , Indóis/farmacologia , Músculo Liso Vascular , Músculo Liso , Animais , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células HEK293 , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Músculo Liso/metabolismo , Músculo Liso/patologia , Músculo Liso/fisiopatologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Ratos , Remodelação Vascular/efeitos dos fármacos
10.
Rev Med Chil ; 147(3): 281-288, 2019 Mar.
Artigo em Espanhol | MEDLINE | ID: mdl-31344164

RESUMO

BACKGROUND: Living above 2,500 meters in hypobaric conditions induces pulmonary arterial hypertension of the neonate (PAHN), a syndrome whose main features are: pathological remodeling of the pulmonary vessels, abnormal vascular reactivity and increased oxidative stress. Melatonin could have pulmonary antioxidant, anti-remodeling and vasodilating properties for this condition. AIM: To determine the effect of melatonin at the transcript level of prostanoid pathways in the lung of neonatal lambs gestated and born under hypobaric hypoxia. MATERIAL AND METHODS: Vehicle (1.4% of ethanol, n = 6) or melatonin (1 mg * kg1, n = 5) were administered from the postnatal day 4 to 21 to lambs gestated and born at 3,600 meters above sea level. After one week of treatment completion, lung tissue was obtained, the transcript and protein levels of prostanoid synthases and receptors were assessed by RT-PCR and Western Blot. RESULTS: Melatonin induced the expression of prostacyclin synthase transcript and increased protein expression of the prostacyclin receptor. In addition, the treatment decreased the expression of transcript and protein of cyclooxygenase-2, without changes in the expression of the prostanoid vasoconstrictor (thromboxane) pathway. CONCLUSIONS: Postnatal treatment with melatonin increases the expression of the prostacyclin-vasodilator pathway without changing the vasoconstrictor thromboxane pathway. Further, the decreased COX-2 induced by melatonin could be an index of lesser oxidative stress and inflammation in the lung.


Assuntos
Antioxidantes/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Melatonina/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Prostaglandinas/metabolismo , Animais , Animais Recém-Nascidos , Hipertensão Pulmonar/metabolismo , Hipóxia , Artéria Pulmonar/efeitos dos fármacos , Ovinos
11.
Int Heart J ; 60(4): 924-937, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31204374

RESUMO

Our previous studies have revealed that long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and genes were abnormally expressed in the pulmonary artery tissues of the chronic thromboembolic pulmonary hypertension (CTEPH) patients. We aim to establish the CTEPH-related miRNA-gene-lncRNA network for finding the core genes and associated miRNA and lncRNA in CTEPH patients.Firstly, the target genes of differential miRNAs were predicted by searching TargetScan databases, and the predicted target genes were intersected with the mRNAs from the gene chip. Secondly, the intersective genes were analyzed by the Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway software for obtaining differential intersective genes and then establish the miRNA-gene networks. Thirdly, the possible genes regulated by the differential lncRNAs from the gene chip were intersected with the above-screened mRNA to build the lncRNA-mRNA networks. Subsequently, the miRNA-gene-lncRNA networks were constructed according to the two networks above (miRNA-gene networks and lncRNA-mRNA networks). Finally, the core genes of the networks in the experimental group were screened according to Diffk > 0.6 and used to construct the miRNA-core gene-lncRNA networks of CTEPH.The pathway network, miRNA-mRNA network, lncRNA-mRNA networks, and miRNA-gene-lncRNA networks were successfully constructed. The core genes of the miRNA-gene-lncRNA networks (Diffk > 0.6) were the human Beta-type platelet-derived growth factor receptor (PDGFRB) and hypoxia-inducible factor-1a (HIF-1A), the miRNAs-PDGFRB-lncRNAs and miRNAs-HIF1A-lncRNAs networks were constructed. Finally, miRNA-149-5p-PDGFRB-TCONS_l2_00020587-XLOC_l2_010723 and miRNA-338-5p/miRNA-199b-5p-HIF1A- TCONS_l2_00020587-XLOC_l2_010723 were found in the analysis of the network.miRNA-149-5p-PDGFRB-lncRNA CTEPH-associated 1 (CTEPHA1) (TCONS_l2_00020587-XLOC_l2_010723) and miRNA-338-5p/miRNA-199b-5p-HIF1A-lncRNA CTEPHA1 are related to the development of CTEPH.


Assuntos
Hipertensão Pulmonar/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-sis/genética , Embolia Pulmonar/complicações , Doença Crônica , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismo , Embolia Pulmonar/genética , Embolia Pulmonar/metabolismo
12.
Life Sci ; 232: 116546, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31176777

RESUMO

Pulmonary arterial hypertension (PAH) is reported to contribute to right ventricular failure and death. PAH of variable degrees is often related to congenital heart disease (CHD). Galectin-3 (Gal-3) has been proven to be of great importance in PAH and CHD. Therefore, we investigated the specific mechanism of Gal-3 in CHD-PAH. Patients with CHD-PAH were enrolled to detect the changes of T-cell subsets, cytokine levels, and other related inflammatory cells in the plasma and to assess the Gal-3 levels in the serum. Next, CHD-PAH mouse models were established and treated with restored or depleted Gal-3 to evaluate the systolic pulmonary artery pressure (sPAP) and right ventricular hypertrophy index (RVHI), to determine levels of IL-4, IL-5, IL-13, AKT and p-AKT along with proliferation of pulmonary artery smooth muscle cells (PASMCs). Finally, we explored the effects of adoptive transfer of CD4+T cells on CHD-PAH in mice with Gal-3 knockdown to further investigate the role of Gal-3 in vivo. Initially, Gal-3 was up-regulated in patients with CHD-PAH. Subsequently, it was demonstrated that restored Gal-3 increased sPAP and RVHI, and promoted proliferation of PASMCs by activating the immune response with elevated levels of IL-4, IL-5, IL-13 and p-AKT. Finally, adoptive transfer of CD4+T cells promoted CD4+T cell perivascular infiltration and the progression of CHD-PAH in mice with Gal-3 knockdown. Collectively, the current study suggests a facilitating role of Gal-3 in pulmonary artery remodeling and progression of CHD-PAH via activation of Th2.


Assuntos
Galectina 3/metabolismo , Cardiopatias Congênitas/metabolismo , Hipertensão Pulmonar/metabolismo , Adulto , Idoso , Animais , Modelos Animais de Doenças , Feminino , Galectina 3/sangue , Galectina 3/imunologia , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/imunologia , Cardiopatias Congênitas/fisiopatologia , Humanos , Hipertensão Pulmonar/imunologia , Hipertensão Pulmonar/fisiopatologia , Imunomodulação/fisiologia , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Miócitos de Músculo Liso/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/fisiopatologia , Remodelação Vascular/fisiologia
13.
Br Poult Sci ; 60(5): 499-505, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31213071

RESUMO

1. The relative expression of angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) was determined using quantitative real-time PCR on tissue from the brain (forebrain, midbrain and hindbrain) to investigate the effect of cold-induced pulmonary hypertension syndrome (PHS) in broilers aged 42 days. Brain angiotensin II (Ang II) and AT1R levels were measured using enzyme immunoassay. 2. The right ventricle/total ventricles (RV/TV) ratio of the heart was increased in broilers exposed to cold stress (PHS group) at the end of the experiment. 3. ACE and renin transcripts in three parts of the brain were significantly increased in the PHS group at 42 d of age compared to controls while AGT transcript was significantly increased only in the hindbrain of PHS birds. The amount of AT1R transcript did not differ between control and PHS groups. 4. The amount of Ang II significantly decreased only in the midbrain of PHS birds compared with controls while the amounts of AT1R were not different between treatments in the three segments of the brain. 5. It was concluded that brain gene expression of AGT (in the hindbrain), renin, and ACE was upregulated in broilers with PHS whereas Ang II and AT1R levels were not changed. These results provided evidence of diminished involvement of the renin-angiotensin system in the pathogenesis of chicken pulmonary hypertension.


Assuntos
Proteínas Aviárias/genética , Encéfalo/metabolismo , Galinhas/genética , Hipertensão Pulmonar/veterinária , Sistema Renina-Angiotensina/genética , Animais , Proteínas Aviárias/metabolismo , Galinhas/metabolismo , Temperatura Baixa/efeitos adversos , Ensaio de Imunoadsorção Enzimática/veterinária , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Reação em Cadeia da Polimerase em Tempo Real/veterinária
14.
Biomed Res Int ; 2019: 2858750, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119161

RESUMO

Pulmonary arterial hypertension (PAH) is a serious condition. However, prevailing therapeutic strategies are not effective enough to treat PAH. Therefore, finding an effective therapy is clearly warranted. Adipose-derived mesenchymal stem cells (ASCs) and ASCs-derived exosomes (ASCs-Exos) exert protective effects in PAH, but the underlying mechanism remains unclear. Using a coculture of ASCs and monocrotaline pyrrole (MCTP)-treated human pulmonary artery endothelial cells (HPAECs), we demonstrated that ASCs increased cell proliferation in MCTP-treated HPAECs. Results showed that ASCs-Exos improved proliferation of both control HPAECs and MCTP-treated HPAECs. In addition, by transfecting ASCs with antagomir we observed that low exosomal miR-191 expression inhibited HPAECs proliferation whereas the agomir improved. Similar results were observed in vivo using a monocrotaline (MCT)-induced PAH rat model following ASCs transplantation. And ASCs transplantation attenuated MCT-induced PAH albeit less than the antagomir treated group. Finally, we found that miR-191 repressed the expression of bone morphogenetic protein receptor 2 (BMPR2) in HPAECs and PAH rats. Thus, we conjectured that miR-191, in ASCs and ASCs-Exos, plays an important role in PAH via regulation of BMPR2. These findings are expected to contribute to promising therapeutic strategies for treating PAH in the future.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Hipertensão Pulmonar/genética , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , Animais , Linhagem Celular , Proliferação de Células/genética , Células Endoteliais/metabolismo , Exossomos/efeitos dos fármacos , Exossomos/genética , Regulação da Expressão Gênica/genética , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Monocrotalina/toxicidade , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Ratos , Ratos Sprague-Dawley
15.
Eur J Med Chem ; 173: 107-116, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30995566

RESUMO

A series of new pyrazolo[3,4-b]pyridin-3-yl pyrimidine derivatives were synthesized and evaluated for the activation of sGC. Compared with riociguat, compound 13a exhibited equivalent in vitro activity on preconstricted rat thoracic aorta rings and in Rat heart Langendorff preparation. Compound 13a also showed acceptable PK profiles, which might become a promising candidate for the treatment of pulmonary hypertension.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Pirazóis/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Guanilil Ciclase Solúvel/metabolismo , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Relação Dose-Resposta a Droga , Hipertensão Pulmonar/metabolismo , Masculino , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
16.
J Biochem Mol Toxicol ; 33(7): e22332, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30974023

RESUMO

Alpha-naphthylthiourea (ANTU), a rodenticide induces lung toxicity. Chrysin a flavonoid possesses antioxidant, anti-inflammatory, and antihypertensive potential. The aim of this study was to evaluate the efficacy of chrysin against ANTU-induced pulmonary edema (PE) and pulmonary arterial hypertension (PAH) in laboratory rats. Sprague-Dawley rats were used to induce PE (ANTU, 10 mg/kg, ip) and PAH (ANTU, 5 mg/kg, ip, 4 weeks). Animals were treated with chrysin (10, 20, and 40 mg/kg) and various biochemical, molecular, and histological parameters were evaluated. Acute administration of ANTU induces PE revealed by significant (P < 0.05) increase in relative lung weight, pleural effusion volume, lung edema, bronchoalveolar lavage fluid cell counts, total protein, 5-hydroxytryptamine (5-HT), lactate dehydrogenase (LDH), and γ-glutamyl transferase (GGT), whereas pretreatment with chrysin (20 and 40 mg/kg, ip) significantly (P < 0.05) attenuated these ANTU-induced biochemical and histological alterations. Repeated administration of ANTU caused induction of PAH evaluated by significant (P < 0.05) alterations in electrocardiographic, hemodynamic changes, and left ventricular function, whereas chrysin (20 and 40 mg/kg, p.o.) treatment significantly (P < 0.05) attenuated these alterations. ANTU-induced hematological and serum biochemical (aspartate transaminase, alanine transaminase, LDH, and creatinine kinase MB) alterations were significantly (P < 0.05) inhibited by chrysin. It also significantly (P < 0.05) decreased elevated levels of oxido-nitrosative stress in the right ventricle (RV) and lung. Chrysin significantly (P < 0.05) attenuated downregulated endothelial nitric oxide synthase and upregulated vascular endothelial growth factor messenger RNA and protein expressions both in the RV and pulmonary artery. Chrysin inhibited ANTU-induced PE and PAH via modulation of inflammatory responses (5-HT, LDH, and GGT), oxido-nitrosative stress, and VEGF and eNOs levels.


Assuntos
Flavonoides/farmacologia , Hipertensão Pulmonar , Óxido Nítrico Sintase Tipo III/biossíntese , Edema Pulmonar , Tioureia/análogos & derivados , Fator A de Crescimento do Endotélio Vascular/biossíntese , Animais , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/prevenção & controle , Pulmão/metabolismo , Pulmão/patologia , Masculino , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Edema Pulmonar/prevenção & controle , Ratos , Ratos Sprague-Dawley , Tioureia/efeitos adversos , Tioureia/farmacologia
17.
Nutr Metab Cardiovasc Dis ; 29(6): 639-651, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30954415

RESUMO

BACKGROUND AND AIMS: Early postnatal life is a critical developmental period that affects health of the whole life. Extrauterine growth restriction (EUGR) causes cardiovascular development problems and diseases, including pulmonary arterial hypertension (PAH). PAH is characterized by proliferation, migration, and anti-apoptosis of pulmonary artery smooth muscle cells (PASMCs). However, the role of PASMCs in EUGR has not been studied. Thus, we hypothesized that PASMCs dysfunction played a role in EUGR-induced pulmonary hypertension. METHODS AND RESULTS: Here we identified that postnatal nutritional restriction-induced EUGR rats exhibited an elevated mean pulmonary arterial pressure and vascular remodeling at 12 weeks old. PASMCs of EUGR rats showed increased cell proliferation and migration features. In EUGR-induced PAH rats, Notch3 signaling was activated. Relative mRNA and protein expression levels of Notch3 intracellular domain (Notch3 ICD), and Notch target gene Hey1 in PASMCs were upregulated. We further demonstrated that pharmacological inhibition of Notch3 activity by using a γ-secretase inhibitor DAPT, which blocked the cleavage of Notch proteins to ICD peptides, could effectively inhibit PASMC proliferation. Specifically knocked down of Notch3 in rat PASMCs by shRNA restored the abnormal PASMC phenotype in vitro. We found that administration of Notch signaling inhibitor DAPT could successfully reduce mean pulmonary arterial pressure in EUGR rats. CONCLUSIONS: The present study demonstrated that upregulation of Notch3 signaling in PASMCs was crucial for the development of EUGR-induced PAH. Blocking Notch3-Hey1 signaling pathway in PASMCs provides a potential therapeutic target for PAH.


Assuntos
Pressão Arterial , Transtornos do Crescimento/complicações , Hipertensão Pulmonar/etiologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Receptor Notch3/metabolismo , Animais , Animais Recém-Nascidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Restrição Calórica , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Transtornos do Crescimento/metabolismo , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Masculino , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Ratos Sprague-Dawley , Receptor Notch3/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Remodelação Vascular
18.
J Vasc Res ; 56(2): 97-106, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31030195

RESUMO

BACKGROUND AND AIMS: Pulmonary hypertension (PH) is a chronic progressing vascular disease characterized by pulmonary arteriole remodeling and loss of pulmonary microvasculature. The aim of this study was to investigate a potential role for the miR-495 in PH pathogenesis and to explore its therapeutic potential in PH. METHODS: Male C57BL/6J mice were injected with SU5416 weekly during 3 weeks of exposure to 10% oxygen to cause PH. We first tested the effects of adeno-associated virus 9 (AAV9) delivery which was specifically designed to block miR-495 in the lungs of the PH model. Then, the biological function of miR-495 was analyzed in cultured pulmonary arterial endothelial cells (PAECs) under hypoxic condition. RESULTS: The inhibition of miR-495 improves hemodynamics and vascular remodeling in PH. At the same time, these effects were associated with increases in angiogenic transcription factor VEZF1 and marked upregulation of other angiogenic genes such as Angpt-1 and IGF1. In vitro, cultured mouse PAECs were transfected with miR-495 inhibitor or miR-495 mimics. Both the flow cytometry results and CCK8 assay showed that miR-495 inhibitor increased the percentage of cells in the G2/M+S phase, and the wound healing assays indicated that the migration capacity of PAECs transfected with miR-495 inhibitor was increased compared to the inhibitor-NC cells. CONCLUSIONS: Our results indicate that AAV9-TuD-miR-495 delivery improves hemodynamic and pulmonary vascular structural changes in PH mice.


Assuntos
Terapia Genética/métodos , Hipertensão Pulmonar/terapia , Pulmão/irrigação sanguínea , MicroRNAs/metabolismo , Microvasos/metabolismo , Neovascularização Fisiológica , Remodelação Vascular , Proteínas Angiogênicas/genética , Proteínas Angiogênicas/metabolismo , Animais , Pontos de Checagem do Ciclo Celular , Movimento Celular , Proliferação de Células , Células Cultivadas , Dependovirus/genética , Modelos Animais de Doenças , Vetores Genéticos , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Hipóxia/complicações , Indóis , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Microvasos/fisiopatologia , Pirróis , Recuperação de Função Fisiológica , Transdução de Sinais
19.
Int J Mol Sci ; 20(8)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013688

RESUMO

Pulmonary arterial hypertension (PAH) results in hypertrophic remodeling of the right ventricle (RV) to overcome increased pulmonary pressure. This increases the O2 consumption of the myocardium, and without a concomitant increase in energy generation, a mismatch with demand may occur. Eventually, RV function can no longer be sustained, and RV failure occurs. Beta-adrenergic blockers (BB) are thought to improve survival in left heart failure, in part by reducing energy expenditure and hypertrophy, however they are not currently a therapy for PAH. The monocrotaline (MCT) rat model of PAH was used to investigate the consequence of RV failure on myocardial oxygenation and mitochondrial function. A second group of MCT rats was treated daily with the beta-1 blocker metoprolol (MCT + BB). Histology confirmed reduced capillary density and increased capillary supply area without indications of capillary rarefaction in MCT rats. A computer model of O2 flux was applied to the experimentally recorded capillary locations and predicted a reduction in mean tissue PO2 in MCT rats. The fraction of hypoxic tissue (defined as PO2 < 0.5 mmHg) was reduced following beta-1 blocker (BB) treatment. The functionality of the creatine kinase (CK) energy shuttle was measured in permeabilized RV myocytes by sequential ADP titrations in the presence and absence of creatine. Creatine significantly decreased the KmADP in cells from saline-injected control (CON) rats, but not MCT rats. The difference in KmADP with or without creatine was not different in MCT + BB cells compared to CON or MCT cells. Improved myocardial energetics could contribute to improved survival of PAH with chronic BB treatment.


Assuntos
Metabolismo Energético , Disfunção Ventricular Direita/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Animais , Creatina Quinase/metabolismo , Modelos Animais de Doenças , Ativação Enzimática , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Monocrotalina/metabolismo , Monocrotalina/farmacologia , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Oxigênio/metabolismo , Ratos
20.
Respir Res ; 20(1): 79, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31023308

RESUMO

BACKGROUND: C-X-C chemokine receptor type 4 (CXCR4) may be involved in the development of pulmonary arterial hypertension (PAH). CXCR4 inhibitor AMD3100 was described to have a positive effect on the prevention of pulmonary arterial muscularization in PAH models. Silibinin is a traditional medicine that has an antagonistic effect on CXCR4. We investigated the effect of silibinin using rat models of PAH. METHODS: PAH was induced by a single subcutaneous injection of monocrotaline. The rats were maintained in a chronic hypoxic condition (10% O2) with or without silibinin. To evaluate the efficacy of silibinin on PAH, right ventricular systolic pressure (RVSP), Fulton index (weight ratio of right ventricle to the left ventricle and septum), percent medial wall thickness (% MT), and vascular occlusion score (VOS) were measured and calculated. Immunohistochemical analysis was performed targeting CXCR4 and c-Kit. Reverse transcription-quantitative polymerase chain reaction was performed for the stem cell markers CXCR4, stromal cell derived factor-1 (SDF-1), c-Kit, and stem cell factor (SCF), and the inflammatory markers monocyte chemoattractant protein 1 (MCP1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα). Statistical analyses were performed using t-test and one-way analysis of variance with Bonferroni's post hoc test. RESULTS: Silibinin treatment for 1 week reduced RVSP and Fulton index. Treatment for 2 weeks reduced RVSP, Fulton index, % MT, and VOS, as well as downregulating the expression of CXCR4, SDF-1, and TNFα in pulmonary arteries. In contrast, treatment for 3 weeks failed to ameliorate PAH. The time-course study demonstrated that RVSP, Fulton index, % MT, and VOS gradually increased over time, with a decrease in the expression of CXCR4 and TNFα occurring after 2 weeks of PAH development. After 3 weeks, SDF-1, c-Kit, and SCF began to decrease and, after 5 weeks, MCP1 and IL-6 gradually accumulated. CONCLUSIONS: The CXCR4 inhibitor silibinin can ameliorate PAH, possibly through the suppression of the CXCR4/SDF-1 axis, until the point where PAH becomes a severe and irreversible condition. Silibinin results in reduced pulmonary arterial pressure and delays pulmonary arteriolar occlusion and pulmonary vascular remodeling.


Assuntos
Modelos Animais de Doenças , Hipertensão Pulmonar/tratamento farmacológico , Hipóxia/tratamento farmacológico , Monocrotalina/toxicidade , Receptores CXCR4/antagonistas & inibidores , Silibina/uso terapêutico , Animais , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/metabolismo , Hipóxia/induzido quimicamente , Hipóxia/metabolismo , Masculino , Substâncias Protetoras/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores CXCR4/fisiologia , Resultado do Tratamento
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