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1.
Am J Physiol Heart Circ Physiol ; 318(4): H925-H936, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32142378

RESUMO

Using high-fidelity micromanometers and flow velocity sensors at right heart catheterization, we compared pulmonary hemodynamics and wave reflections in age-matched normal adults and those with atrial septal defects, separated into three subgroups based on levels of mean pulmonary artery pressure: low (<17 mmHg), intermediate (17-26 mmHg), high (>26 mmHg). We made baseline measurements in all groups and after intravenous sodium nitroprusside in the subgroups. All of the subgroups had higher than normal baseline pulmonary flows and corresponding power that did not differ among the subgroups. The pulmonary vascular resistance, input resistance, and characteristic impedance in the subgroups did not differ from normal. Aside from the elevated flow and power, the hemodynamics in the low subgroup did not differ from normal. The intermediate subgroup had significantly higher than normal right ventricular and pulmonary artery pressures, wave reflections, and shorter wave reflection time, which all reverted to normal after nitroprusside. The high subgroup had similar changes as the intermediate subgroup. Unlike that subgroup, however, the pressures, wave reflections, and reflection return time did not revert to normal after nitroprusside. Hence, elevated wave reflections, but not resistance or characteristic impedance, are the hallmark of pulmonary hypertension in adults with atrial septal defects. Our results demonstrate that detailed measurements of hemodynamics and assessment of responsiveness to vasodilators provide important information about the pulmonary circulation in atrial septal defect. Coupled with studies after defect closure, those results may be a better foundation than current ones for clinical decisions.


Assuntos
Comunicação Interatrial/fisiopatologia , Hemodinâmica , Circulação Pulmonar , Adulto , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Nitroprussiato/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Vasodilatadores/farmacologia
2.
Am J Physiol Heart Circ Physiol ; 318(4): H853-H866, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32108526

RESUMO

Right ventricular (RV) dysfunction is the main determinant of mortality in patients with pulmonary arterial hypertension (PAH) and while inflammation is pathogenic in PAH, there is limited information on the role of RV inflammation in PAH. Sulforaphane (SFN), a potent Nrf2 activator, has significant anti-inflammatory effects and facilitates cardiac protection in preclinical diabetic models. Therefore, we hypothesized that SFN might play a comparable role in reducing RV and pulmonary inflammation and injury in a murine PAH model. We induced PAH using SU5416 and 10% hypoxia (SuHx) for 4 wk in male mice randomized to SFN at a daily dose of 0.5 mg/kg 5 days per week for 4 wk or to vehicle control. Transthoracic echocardiography was performed to characterize chamber-specific ventricular function during PAH induction. At 4 wk, we measured RV pressure and relevant measures of histology and protein and gene expression. SuHx induced progressive RV, but not LV, diastolic and systolic dysfunction, and RV and pulmonary remodeling, fibrosis, and inflammation. SFN prevented SuHx-induced RV dysfunction and remodeling, reduced RV inflammation and fibrosis, upregulated Nrf2 expression and its downstream gene NQO1, and reduced the inflammatory mediator leucine-rich repeat and pyrin domain-containing 3 (NLRP3). SFN also reduced SuHx-induced pulmonary vascular remodeling, inflammation, and fibrosis. SFN alone had no effect on the heart or lungs. Thus, SuHx-induced RV and pulmonary dysfunction, inflammation, and fibrosis can be attenuated or prevented by SFN, supporting the rationale for further studies to investigate SFN and the role of Nrf2 and NLRP3 pathways in preclinical and clinical PAH studies.NEW & NOTEWORTHY Pulmonary arterial hypertension (PAH) in this murine model (SU5416 + hypoxia) is associated with early changes in right ventricular (RV) diastolic and systolic function. RV and lung injury in the SU5416 + hypoxia model are associated with markers for fibrosis, inflammation, and oxidative stress. Sulforaphane (SFN) alone for 4 wk has no effect on the murine heart or lungs. Sulforaphane (SFN) attenuates or prevents the RV and lung injury in the SUF5416 + hypoxia model of PAH, suggesting that Nrf2 may be a candidate target for strategies to prevent or reverse PAH.


Assuntos
Anti-Inflamatórios/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Isotiocianatos/uso terapêutico , Artéria Pulmonar/efeitos dos fármacos , Remodelação Vascular , Disfunção Ventricular Direita/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Hipertensão Pulmonar/complicações , Isotiocianatos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Artéria Pulmonar/patologia , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/prevenção & controle
3.
Life Sci ; 246: 117419, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32045592

RESUMO

AIMS: Although resistin-like molecule ß (RELM-ß) is involved in the pathological processes of various lung diseases, such as pulmonary inflammation, asthma and fibrosis, its potential roles in hypoxic pulmonary arterial hypertension (PAH) remain largely unknown. The study aims to investigate whether RELM-ß contributes to hypoxia-induced excessive proliferation of human pulmonary artery smooth muscle cells (PASMCs) and to explore the potential mechanisms of this process. MAIN METHODS: Human PASMCs were exposed to normoxia or hypoxia (1% O2) for 24 h. siRNA targeting RELM-ß was transfected into cells. Protein levels of KCNK3, RELM-ß, pSTAT3 and STAT3 were determined by immunoblotting. The translocation of NFATc2 and expression of KCNK3 were visualized by immunofluorescence. 5-ethynyl-2'-deoxyuridine assays and cell counting kit-8 assays were performed to assess the proliferation of PASMCs. KEY FINDINGS: (1) Chronic hypoxia significantly decreased KCNK3 protein levels while upregulating RELM-ß protein levels in human PASMCs, which was accompanied by excessive proliferation of cells. (2) RELM-ß could promote human PASMCs proliferation and activate the STAT3/NFAT axis by downregulating KCNK3 protein under normoxia. (3) Inhibition of RELM-ß expression effectively prevented KCNK3-mediated cell proliferation under hypoxia. (4) Phospholipase C (PLC) inhibitor U-73122 could not only prevent the hypoxia/RELM-ß-induced decrease in KCNK3 protein, but also inhibit the enhanced cell viability caused by hypoxia/RELM-ß. (5) Both hypoxia and RELM-ß could downregulate membrane KCNK3 protein levels by enhancing endocytosis. SIGNIFICANCE: RELM-ß activation is responsible for hypoxia-induced excessive proliferation of human PASMCs. Interfering with RELM-ß may alleviate the progression of hypoxic PAH by upregulating PLC-dependent KCNK3 expression.


Assuntos
Hipóxia/complicações , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Fosfolipases Tipo C/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Imunofluorescência , Humanos , Hipóxia/tratamento farmacológico , Músculo Liso Vascular/citologia , Músculo Liso Vascular/crescimento & desenvolvimento , Artéria Pulmonar/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais
4.
Am J Physiol Heart Circ Physiol ; 318(2): H470-H483, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31922892

RESUMO

Reactive oxygen species (ROS), mitochondrial dysfunction, and excessive vasoconstriction are important contributors to chronic hypoxia (CH)-induced neonatal pulmonary hypertension. On the basis of evidence that PKCß and mitochondrial oxidative stress are involved in several cardiovascular and metabolic disorders, we hypothesized that PKCß and mitochondrial ROS (mitoROS) signaling contribute to enhanced pulmonary vasoconstriction in neonatal rats exposed to CH. To test this hypothesis, we examined effects of the PKCß inhibitor LY-333,531, the ROS scavenger 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine (TEMPOL), and the mitochondrial antioxidants mitoquinone mesylate (MitoQ) and (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (MitoTEMPO) on vasoconstrictor responses in saline-perfused lungs (in situ) or pressurized pulmonary arteries from 2-wk-old control and CH (12-day exposure, 0.5 atm) rats. Lungs from CH rats exhibited greater basal tone and vasoconstrictor sensitivity to 9,11-dideoxy-9α,11α-methanoepoxy prostaglandin F2α (U-46619). LY-333,531 and TEMPOL attenuated these effects of CH, while having no effect in lungs from control animals. Basal tone was similarly elevated in isolated pulmonary arteries from neonatal CH rats compared with control rats, which was inhibited by both LY-333,531 and mitochondria-targeted antioxidants. Additional experiments assessing mitoROS generation with the mitochondria-targeted ROS indicator MitoSOX revealed that a PKCß-mitochondrial oxidant signaling pathway can be pharmacologically stimulated by the PKC activator phorbol 12-myristate 13-acetate in primary cultures of pulmonary artery smooth muscle cells (PASMCs) from control neonates. Finally, we found that neonatal CH increased mitochondrially localized PKCß in pulmonary arteries as assessed by Western blotting of subcellular fractions. We conclude that PKCß activation leads to mitoROS production in PASMCs from neonatal rats. Furthermore, this signaling axis may account for enhanced pulmonary vasoconstrictor sensitivity following CH exposure.NEW & NOTEWORTHY This research demonstrates a novel contribution of PKCß and mitochondrial reactive oxygen species signaling to increased pulmonary vasoconstrictor reactivity in chronically hypoxic neonates. The results provide a potential mechanism by which chronic hypoxia increases both basal and agonist-induced pulmonary arterial smooth muscle tone, which may contribute to neonatal pulmonary hypertension.


Assuntos
Hipóxia/metabolismo , Proteína Quinase C beta/metabolismo , Animais , Animais Recém-Nascidos , Doença Crônica , Óxidos N-Cíclicos/farmacologia , Inibidores Enzimáticos , Feminino , Depuradores de Radicais Livres , Indóis/farmacologia , Maleimidas/farmacologia , Compostos Organofosforados/farmacologia , Estresse Oxidativo , Gravidez , Proteína Quinase C beta/antagonistas & inibidores , Artéria Pulmonar/efeitos dos fármacos , Circulação Pulmonar , Ratos , Espécies Reativas de Oxigênio , Marcadores de Spin , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Vasoconstrição , Vasoconstritores/farmacologia
5.
Am J Physiol Lung Cell Mol Physiol ; 318(2): L386-L401, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913656

RESUMO

Pulmonary hypertension (PH) is a multicellular and progressive disease with a high mortality rate. Among many cell types, hematopoietic stem cells (HSCs) are incriminated in the pathogenesis of PH. However, our understanding of the mechanisms that increase HSCs in blood and lungs of hypertensive animals or patients and the role played by HSCs in the pathogenesis of PH remains elusive. Studies suggest that glycolysis is critical for the survival and growth of HSCs. In various cell types from hypertensive lungs of animals and patients, glycolysis and the glucose-6-phosphate dehydrogenase (G6PD) activity are increased. Herein, we demonstrated in mice that chronic hypoxia increased HSCs (CD34+, CD117+, CD133+, CD34+/CD117+, and CD34+/CD133+) in bone marrow and blood and around hypertensive pulmonary arteries in a time-dependent manner. Intriguingly, we found fewer CD133+ cells in the bone marrow of C57BL/6 mice compared with Sv129J mice, and C57BL mice developed less severe chronic hypoxia-elicited PH and heart failure than Sv129J mice. Similarly, the numbers of CD34+ and CD117+ cells in blood of patients with pulmonary arterial hypertension (PAH) were higher (>3-fold) compared with healthy individuals. By allogeneic bone marrow transplantation, we found that GFP+ bone marrow cells infiltrated the lungs and accumulated around the pulmonary arteries in lungs of hypoxic mice, and these cells contributed to increased α-adrenergic receptor-mediated contraction of the pulmonary artery cultured in hypoxia. Inhibition of G6PD activity with (3ß,5α)-3,21-dihydroxypregnan-20-one, a novel and potent G6PD inhibitor, decreased HSCs in bone marrow, blood, and lungs of hypoxic mice and reduced α-agonist-induced contraction of the pulmonary artery and established hypoxia-induced PH. We did not observe CD133+ cells around the pulmonary arteries in the lungs of chronically hypoxic G6PD-deficient mice. Furthermore, knockdown of G6PD and inhibition of G6PD activity: 1) downregulated canonical and noncanonical Wnt and Fzd receptors genes; 2) upregulated Bmpr1a; 3) decreased Cxcl12, and 4) reduced HSC (CD117+ and CD133+) numbers. In all, our findings demonstrate unexpected function for bone marrow-derived HSCs in augmenting α-adrenergic receptor-mediated contraction of pulmonary arteries and remodeling of pulmonary arteries that contribute to increase pulmonary vascular resistance in PAH patients and hypoxic mice and suggest that G6PD, by regulating expression of genes in the WNT and BMPR signaling, contributed to increase and release of HSCs from the bone marrow in response to hypoxic stimuli.


Assuntos
Células-Tronco Hematopoéticas/metabolismo , Hipertensão Pulmonar/fisiopatologia , Células-Tronco Pluripotentes/metabolismo , Artéria Pulmonar/fisiopatologia , Receptores Adrenérgicos alfa/metabolismo , Animais , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Contagem de Células , Células Cultivadas , Quimiocina CXCL12/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosefosfato Desidrogenase/antagonistas & inibidores , Glucosefosfato Desidrogenase/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Coração/fisiopatologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Hipertensão Pulmonar/etiologia , Hipóxia/sangue , Hipóxia/complicações , Hipóxia/genética , Pulmão/patologia , Pulmão/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Pluripotentes/efeitos dos fármacos , Artéria Pulmonar/efeitos dos fármacos , Via de Sinalização Wnt/genética
6.
Toxicol In Vitro ; 62: 104668, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31629073

RESUMO

Methamphetamine (MA) has a high uptake in lung, but the precise mechanism of MA-induced lung toxicity remains unclear. The aim of this study is to investigate the role of MA abuse in remodeling of pulmonary arteries and to explore the possible correlation of the association of the remodeling with the redox imbalance in pulmonary arterial smooth muscle cells (PASMCs). Wistar rats were randomly divided into control group and MA group for the experimental study. We employed H&E staining, western blot, immunofluorescence, knockdown, flow in our experimental approach. Our studies shows that chronic exposure to MA led to weight loss, increased pulmonary arterial pressure, hypertrophy of right ventricle and remodeling of pulmonary arterial wall of rats. Our cell culture study with PASMCs indicates that MA significantly induced the imbalance between proliferation and apoptosis by upregulating the level of PCNA, Bcl-2 and reduction in the expression of BAX and Caspase 3. MA markedly prevented the nuclear translocation of Nrf2 to inhibit antioxidation. The knockdown of Nrf2 expression using siRNA significantly elevated the expression of SOD2/GCS and the production of ROS in PASMCs and even scaled up the amount of PASMCs induced by MA. Linear regression analysis showed that knockdown of Nrf2 promoted the positive correlation of relative ROS level with proliferation of PASMCs. Therefore, chronic exposure to MA induces pulmonary arterial remodeling by Nrf2-mediated imbalance of redox system to aggravate oxidative stress, and Nrf2 is a possible target for the treatment of MA-lung toxicity.


Assuntos
Estimulantes do Sistema Nervoso Central/toxicidade , Metanfetamina/toxicidade , Miócitos de Músculo Liso/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Masculino , Miócitos de Músculo Liso/metabolismo , Fator 2 Relacionado a NF-E2/genética , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
7.
Biomed Res Int ; 2019: 1219848, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31886168

RESUMO

Pulmonary artery hypertension is a refractory disease that severely affects cardiopulmonary function, mainly resulting in irreversible pulmonary vascular remodeling. Current surgical treatment of this disease is not very effective and drug treatment is targeted at relieving symptoms, improving the quality of life of patients, and preventing disease progression. The purpose of this present study was to reveal the regulatory effects of trimethoxystilbene on the serum levels of nuclear factor kappa B, interleukin-6, and tumor necrosis factor-α in a rat model of pulmonary artery hypertension and to explore the possible underlying mechanisms. Healthy Sprague Dawley rats were randomly assigned to experimental groups and treated with monocrotaline to establish the model, and we found a significant difference in the expression levels of nuclear factor kappa B, interleukin-6, and tumor necrosis factor-α between the experimental and control groups. These results suggest that trimethoxystilbene significantly reduced the inflammatory factor levels in pulmonary hypertensive rats, providing us with new potential strategies for elucidating the mechanisms of action of trimethoxystilbene in the treatment of pulmonary artery hypertension.


Assuntos
Interleucina-6/metabolismo , NF-kappa B/metabolismo , Hipertensão Arterial Pulmonar/tratamento farmacológico , Artéria Pulmonar/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Imuno-Histoquímica , Interleucina-6/sangue , Pulmão/patologia , Masculino , Monocrotalina/uso terapêutico , NF-kappa B/sangue , Gravidez , Hipertensão Arterial Pulmonar/patologia , Artéria Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/sangue
8.
Artigo em Inglês | MEDLINE | ID: mdl-31569724

RESUMO

Background: The developing lung is uniquely susceptible and may be at increased risk of injury with exposure to e-cigarette constituents. We hypothesize that cellular toxicity and airway and vascular responses with exposure to flavored refill solutions may be altered in the immature lung. Methods: Fetal, neonatal, and adult ovine pulmonary artery smooth muscle cells (PASMC) were exposed to popular flavored nicotine-free e-cigarette refill solutions (menthol, strawberry, tobacco, and vanilla) and unflavored solvents: propylene glycol (PG) or vegetable glycerin (VG). Viability was assessed by lactate dehydrogenase assay. Brochodilation and vasoreactivity were determined on isolated ovine bronchial rings (BR) and pulmonary arteries (PA). Results: Neither PG or VG impacted viability of immature or adult cells; however, exposure to menthol and strawberry flavored solutions increased cell death. Neonatal cells were uniquely susceptible to menthol flavoring-induced toxicity, and all four flavorings demonstrated lower lethal doses (LD50) in immature PASMC. Exposure to flavored solutions induced bronchodilation of neonatal BR, while only menthol induced airway relaxation in adults. In contrast, PG/VG and flavored solutions did not impact vasoreactivity with the exception of menthol-induced relaxation of adult PAs. Conclusion: The immature lung is uniquely susceptible to cellular toxicity and altered airway responses with exposure to common flavored e-cigarette solutions.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Desenvolvimento Fetal/efeitos dos fármacos , Aromatizantes/toxicidade , Pulmão/efeitos dos fármacos , Pulmão/embriologia , Mentol/toxicidade , Animais , Animais Recém-Nascidos , Técnicas In Vitro , Pulmão/crescimento & desenvolvimento , Miócitos de Músculo Liso/efeitos dos fármacos , Artéria Pulmonar/efeitos dos fármacos , Ovinos , Testes de Toxicidade
9.
Int J Mol Sci ; 20(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540416

RESUMO

We investigated whether magnesium sulfate (MgSO4) mitigated pulmonary hypertension progression in rats. Pulmonary hypertension was induced by a single intraperitoneal injection of monocrotaline (60 mg/kg). MgSO4 (100 mg/kg) was intraperitoneally administered daily for 3 weeks, from the seventh day after monocrotaline injection. Adult male rats were randomized into monocrotaline (MCT) or monocrotaline plus MgSO4 (MM) groups (n = 15 per group); control groups were maintained simultaneously. For analysis, surviving rats were euthanized on the 28th day after receiving monocrotaline. The survival rate was higher in the MM group than in the MCT group (100% versus 73.3%, p = 0.043). Levels of pulmonary artery wall thickening, α-smooth muscle actin upregulation, right ventricular systolic pressure increase, and right ventricular hypertrophy were lower in the MM group than in the MCT group (all p < 0.05). Levels of lipid peroxidation, mitochondrial injury, inflammasomes and cytokine upregulation, and apoptosis in the lungs and right ventricle were lower in the MM group than in the MCT group (all p < 0.05). Notably, the mitigation effects of MgSO4 on pulmonary artery wall thickening and right ventricular hypertrophy were counteracted by exogenous calcium chloride. In conclusion, MgSO4 mitigates pulmonary hypertension progression, possibly by antagonizing calcium.


Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Sulfato de Magnésio/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Progressão da Doença , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/patologia , Masculino , Monocrotalina , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Ratos , Ratos Sprague-Dawley
10.
Int J Rheum Dis ; 22(9): 1775-1781, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31368254

RESUMO

AIM: This study aimed to retrospectively describe 15 new primary Sjögren's syndrome-pulmonary arterial hypertension (pSS-PAH) cases confirmed by right heart catheterization (RHC). Demographic and clinical characteristics were analyzed and risk factors for PAH in pSS were explored. METHOD: We retrospectively described 15 new pSS-PAH cases confirmed by RHC referred to our institution between January 2013 and March 2018. We present PAH and pSS characteristics, hemodynamic evaluations, medical management, and outcomes. A matched case control study was carried out to determine the risk factors of PAH in pSS compared with pSS-non-PAH patients. RESULTS: All patients were female with a mean age at PAH diagnosis of 52.9 ± 14.6 years. The delay between the first symptom and PAH diagnosis was 18.7 ± 19.7 months. The most common primary manifestation at PAH onset was exertional dyspnea (13/15). At diagnosis of PAH, PAH was severe with a mean pulmonary artery pressure of 48.8 ± 13.7 mm Hg (range, 27-72 mm Hg) and a mean cardiac index of 2.3 ± 0.6 L/min/m2 (range, 1.47-3.41 L/min/m2 ). Compared with the pSS-PAH without pericardial effusion, pSS-PAH with pericardial effusion had larger right arterial (53 [45-56.75] vs 38 [35.5-46.5], P = .018) and right ventricular sizes (47 [42.75-51.25] vs 36 [32.5-41], P = .007). Compared with the pSS non-PAH group, we identified 2 risk factors for PAH in pSS: pericardial effusion (odds ratio [OR] [95% CI], 14.29 [1.14-166.67], P = .039) and liver involvement (OR [95% CI], 14.71 [1.14-166.67], P = .035). CONCLUSION: For pSS patients, PAH can be the first manifestation. We believe that systemic evaluation, especially in patients with pericardial effusion and liver involvement, is important to identify high-risk patients for PAH, improving their prognosis.


Assuntos
Pressão Arterial , Artéria Pulmonar/fisiopatologia , Síndrome de Sjogren/complicações , Adulto , Idoso , Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , China , Dispneia/etiologia , Dispneia/fisiopatologia , Feminino , Humanos , Imunossupressores/uso terapêutico , Hepatopatias/etiologia , Hepatopatias/fisiopatologia , Pessoa de Meia-Idade , Derrame Pericárdico/etiologia , Derrame Pericárdico/fisiopatologia , Prognóstico , /tratamento farmacológico , Artéria Pulmonar/efeitos dos fármacos , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/tratamento farmacológico
11.
Life Sci ; 235: 116794, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31465731

RESUMO

Amongst the various forms of lung injury; pulmonary fibrosis remains the most intricate form with limited therapeutic options to both the patient and the physicians. Bleomycin (BLM) is a chemotherapeutic agent used for the treatment of various carcinomas; however, its therapeutic value is significantly limited by its associated pulmonary fibrosis. The current study highlights the prominent antioxidant, anti-inflammatory and anti-fibrotic effect of crocin against BLM-induced pulmonary fibrosis. Intratracheal BLM instillation induced significant biochemical, structural, functional and vascular pulmonary injury. BLM instillation increased oxidant load with quenching of antioxidant defenses together with increase inflammatory and fibrotic cytokines expression. Crocin significantly attenuated BLM-induced lung injury and its effect was comparable to the standard anti-fibrotic; halofuginone. The observed anti-inflammatory and anti-fibrotic and antioxidant impacts are thought to be embroiled in the therapeutic impacts of crocin. Down-regulation of TLR4, IL-10 expression is the major pathway involved in the observed anti-inflammatory effects and finally, down-regulation of tissue expression of TNF-α and TGF-ß1 is the major pathways implicated in the observed anti-fibrotic activities and modulation of Nrf2 and HO-1 pathways is the main mechanism involved in the observed antioxidant effects.


Assuntos
Bleomicina/toxicidade , Carotenoides/farmacologia , Pneumonia/prevenção & controle , Artéria Pulmonar/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Doenças Vasculares/prevenção & controle , Animais , Antibióticos Antineoplásicos , Masculino , Pneumonia/induzido quimicamente , Pneumonia/patologia , Artéria Pulmonar/patologia , Fibrose Pulmonar/complicações , Fibrose Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Doenças Vasculares/induzido quimicamente , Doenças Vasculares/patologia
12.
Acta Pharmacol Sin ; 40(10): 1322-1333, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31316183

RESUMO

Abnormal wound healing by pulmonary artery smooth muscle cells (PASMCs) promotes vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Increasing evidence shows that both the mammalian target of rapamycin complex 1 (mTORC1) and nuclear factor-kappa B (NF-κB) are involved in the development of HPH. In this study, we explored the crosstalk between mTORC1 and NF-κB in PASMCs cultured under hypoxic condition and in a rat model of hypoxia-induced pulmonary hypertension (HPH). We showed that hypoxia promoted wound healing of PASMCs, which was dose-dependently blocked by the mTORC1 inhibitor rapamycin (5-20 nM). In PASMCs, hypoxia activated mTORC1, which in turn promoted the phosphorylation of NF-κB. Molecular docking revealed that mTOR interacted with IκB kinases (IKKs) and that was validated by immunoprecipitation. In vitro kinase assays and mass spectrometry demonstrated that mTOR phosphorylated IKKα and IKKß separately. Inhibition of mTORC1 decreased the level of phosphorylated IKKα/ß, thus reducing the phosphorylation and transcriptional activity of NF-κB. Bioinformatics study revealed that dipeptidyl peptidase-4 (DPP4) was a target gene of NF-κB; DPP4 inhibitor, sitagliptin (10-500 µM) effectively inhibited the abnormal wound healing of PASMCs under hypoxic condition. In the rat model of HPH, we showed that NF-κB activation (at 3 weeks) was preceded by mTOR signaling activation (after 1 or 2 weeks) in lungs, and administration of sitagliptin (1-5 mg/kg every day, ig) produced preventive effects against the development of HPH. In conclusion, hypoxia activates the crosstalk between mTORC1 and NF-κB, and increased DPP4 expression in PASMCs that leads to vascular remodeling. Sitagliptin, a DPP4 inhibitor, exerts preventive effect against HPH.


Assuntos
Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Administração Oral , Animais , Hipóxia Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Biologia Computacional , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/farmacologia , Modelos Animais de Doenças , Células HEK293 , Humanos , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , NF-kappa B/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Cicatrização/efeitos dos fármacos
13.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(3): 209-214, 2019 May 28.
Artigo em Chinês | MEDLINE | ID: mdl-31257800

RESUMO

OBJECTIVE: To investigate the effects of apple polyphenols on pulmonary vascular remodeling in rats with pulmonary arterial hypertension and its mechanism. METHODS: Rats were randomly divided into 4 groups:control (Con) group, monocrotaline (MCT) group, apple polyphenol (APP) group,monocrotaline + apple polyphenol (MCT+APP) group. In Con group, rats received a subcutaneous injection of physical saline. In APP group, rats received intraperitoneal injection of 20 mg/kg APP, every other day. In MCT group, rats received a single subcutaneous injection of MCT(60 mg/kg). In MCT+APP group, rats received subcutaneous injection of 60 mg/kg MCT followed by an intraperitoneal injection of 20 mg/kg APP every other day. All the disposal lasted 3 weeks. Then the PAH-relevant indicators, such as mean pulmonary artery pressure(mPAP), pulmonary vascular resistance(PVR), right ventricular hypertrophy index (RVHI) ,wall thickness (WT%) and wall area (WA%) were tested. After that, the inflammatory pathway related indicators, such as interleukin1(IL-1),interleukin1(IL-6), tumor necrosis factor α(TNF-α), cyclooxygenase 2(COX-2) and myeloperoxidase(MPO) in pulmonary tissue and free intracellular Ca2+ in pulmonary smooth muscle cell(PASMC), content of eNOS and NO in endothelial cells were determined. RESULTS: Compared with the control group, the levels of mPAP, PVR, RVHI, WA%, WT%, and IL-1, IL-6, TNF-α, COX-2, MPO in tissue and the expression of Ca2 + in PASMC of MCT group were increased significantly, while the contents of eNOS and NO in endothelial cells were decreased significantly (P<0.05). Compared with the MCT group, the apple polyphenol treatment could improve the above mentioned situation, and the COX-2 and Ca2+ indicators of the apple polyphenol treatment group were decreased significantly (P<0.05). CONCLUSION: MCT can increase COX-2 expression and intracellular Ca2+ in pulmonary artery smooth muscle cells, decrease the contents of eNOS and NO in endothelial cells, while apple polyphenols can significantly inhibit these effects.


Assuntos
Malus/química , Polifenóis/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Animais , Cálcio/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Monocrotalina , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Artéria Pulmonar/patologia , Distribuição Aleatória , Ratos
14.
PLoS One ; 14(7): e0213414, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291253

RESUMO

In acidosis, catecholamines are attenuated, and higher doses are often required to improve cardiovascular function. Colforsin activates adenylate cyclase in cardiomyocytes without beta-adrenoceptor. Here, six beagles were administered colforsin or dobutamine four times during eucapnia (partial pressure of arterial carbon dioxide 35-40 mm Hg; normal) and hypercapnia (ibid 90-110 mm Hg; acidosis) conditions. The latter was induced by CO2 inhalation. Anesthesia was induced with propofol and maintained with isoflurane. Cardiovascular function was measured by thermodilution and a Swan-Ganz catheter at baseline and 60 min after 0.3 µg/kg/min (low), 0.6 µg/kg/min (middle), and 1.2 µg/kg/min (high) colforsin administration. The median pH was 7.38 [range 7.33-7.42] and 7.01 [range 6.96-7.08] at baseline in the Normal and Acidosis conditions, respectively. Endogenous adrenaline and noradrenaline levels at baseline were significantly (P < 0.05) higher in the Acidosis than in the Normal condition. Colforsin induced cardiovascular effects similar to those caused by dobutamine. Colforsin increased cardiac output in the Normal condition (baseline: 3.9 ± 0.2 L/kg/m2 [mean ± standard error], low: 5.2 ± 0.4 L/kg/min2, middle: 7.0 ± 0.4 L/kg/m2, high: 9.4 ± 0.2 L/kg/m2; P < 0.001) and Acidosis condition (baseline: 6.1 ± 0.3 L/kg/m2, low: 6.2 ± 0.2 L/kg/m2, middle: 7.2 ± 0.2 L/kg/m2, high: 8.3 ± 0.2 L/kg/m2; P < 0.001). Colforsin significantly increased heart rate and decreased systemic vascular resistance compared to values at baseline. Both drugs increased pulmonary artery pressure, but colforsin (high: 13.3 ± 0.6 mmHg in Normal and 20.1 ± 0.2 mmHg in Acidosis) may have lower clinical impact on the pulmonary artery than dobutamine (high: 19.7 ± 0.6 in Normal and 26.7 ± 0.5 in Acidosis). Interaction between both drugs and experimental conditions was observed in terms of cardiovascular function, which were similarly attenuated with colforsin and dobutamine under acute respiratory acidosis.


Assuntos
Acidose Respiratória/tratamento farmacológico , Cardiotônicos/administração & dosagem , Colforsina/análogos & derivados , Acidose Respiratória/fisiopatologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Catecolaminas/sangue , Colforsina/administração & dosagem , Modelos Animais de Doenças , Dobutamina/administração & dosagem , Cães , Relação Dose-Resposta a Droga , Feminino , Frequência Cardíaca/efeitos dos fármacos , Masculino , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Resistência Vascular/efeitos dos fármacos
15.
Korean J Intern Med ; 34(4): 696-707, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31272141

RESUMO

Pulmonary arterial hypertension (PAH) is characterized by remodeling of the distal pulmonary arteries resulting in high pulmonary vascular resistance and, eventually, right ventricular heart failure. Although current advances in PAH therapy have improved outcomes, poor survival remains a reality worldwide, including Korea. One of the most important issues in PAH is the late diagnosis, since screening or diagnostic efforts are often overlooked due to the rarity of disease. Data from Korean registries and observational cohorts show that delayed detection leads to increased morbidity. Additionally, low percentages of Korean patients are committed to intensive PAH-targeted therapy. Current Korean health insurance policies' lack of coverage for new PAH-targeted drugs and upfront combination therapy may also hamper the improvement of treatment outcomes. Understanding individual variability in response to therapeutics through deep phenotyping is a novel strategy that should be considered when treating PAH. Overall, early detection of PAH by proactive screening together with early, intensive, individualized PAH therapy using deep phenotyping is crucial for improving prognoses for PAH patients in Korea.


Assuntos
Anti-Hipertensivos/uso terapêutico , Artéria Pulmonar/efeitos dos fármacos , Adulto , Idoso , Anti-Hipertensivos/efeitos adversos , Pressão Arterial/efeitos dos fármacos , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , /epidemiologia , Artéria Pulmonar/fisiopatologia , República da Coreia/epidemiologia , Fatores de Risco , Resultado do Tratamento , Remodelação Vascular/efeitos dos fármacos , Adulto Jovem
16.
J Biochem Mol Toxicol ; 33(10): e22380, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31339623

RESUMO

Lung endothelial barrier dysfunction leads to severe pathologies, including the lethal Acute Respiratory Distress Syndrome. P53 has been associated with anti-inflammatory activities. The current study employs a variety of unfolded protein response (UPR) activators and inhibitors to investigate the regulation of P53 by UPR in lung cells. The bovine cells that were exposed to the UPR inductors brefeldin A, dithiothreitol, and thapsigargin; demonstrated elevated expression levels of P53 compared to the vehicle-treated cells. On the contrary, the UPR inhibitors N-acetyl cysteine, kifunensine, and ATP-competitive IRE1α kinase-inhibiting RNase attenuator; produced the opposite effects. The outcomes of the present study reveal a positive regulation between UPR and P53. Since it has been shown that a mild induction of the unfolded protein response opposes inflammation, we suggest that P53 is involved in those protective activities in the lung.


Assuntos
Genes p53 , Artéria Pulmonar/metabolismo , Resposta a Proteínas não Dobradas , Acetilcisteína/farmacologia , Alcaloides/farmacologia , Animais , Brefeldina A/farmacologia , Bovinos , Células Cultivadas , Ditiotreitol/farmacologia , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Artéria Pulmonar/citologia , Artéria Pulmonar/efeitos dos fármacos , Tapsigargina/farmacologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos
17.
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
18.
Biomater Sci ; 7(9): 3640-3651, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31165794

RESUMO

Tissue regeneration requires scaffolds that exhibit mechanical properties similar to the tissues to be replaced while allowing cell infiltration and extracellular matrix production. Ideally, the scaffolds' porous architecture and physico-chemical properties can be precisely defined to address regenerative needs. We thus developed techniques to produce hybrid fibers coaxially structured with a polycaprolactone core and a 4-arm, polyethylene glycol thiol-norbornene sheath. We assessed the respective effects of crosslink density and sheath polymer size on the scaffold architecture, physical and mechanical properties, as well as cell-scaffold interactions in vitro and in vivo. All scaffolds displayed high elasticity, swelling and strength, mimicking soft tissue properties. Importantly, the thiol-ene hydrogel sheath enabled tunable softness and peptide tethering for cellular activities. With increased photopolymerization, stiffening and reduced swelling of scaffolds were found due to intra- and inter-fiber crosslinking. More polymerized scaffolds also enhanced the cell-scaffold interaction in vitro and induced spontaneous, deep cell infiltration to produce collagen and elastin for tissue regeneration in vivo. The molecular weight of sheath polymer provides an additional mechanism to alter the physical properties and biological activities of scaffolds. Overall, these robust scaffolds with tunable elasticity and regenerative cues offered a versatile and effective platform for tissue regeneration.


Assuntos
Reagentes para Ligações Cruzadas/farmacologia , Microfibrilas/química , Poliésteres/farmacologia , Polietilenoglicóis/farmacologia , Compostos de Sulfidrila/farmacologia , Animais , Bovinos , Adesão Celular/efeitos dos fármacos , Reagentes para Ligações Cruzadas/síntese química , Reagentes para Ligações Cruzadas/química , Células Endoteliais/efeitos dos fármacos , Peso Molecular , Poliésteres/química , Polietilenoglicóis/química , Artéria Pulmonar/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Compostos de Sulfidrila/química
19.
Basic Clin Pharmacol Toxicol ; 125(3): 202-214, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31206240

RESUMO

Current treatment of pulmonary arterial hypertension (PAH) targets three signalling pathways: the nitric oxide (NO) pathway, the endothelin pathway and the prostacyclin pathway. Riociguat is a soluble guanylate cyclase stimulator, acting via the NO pathway in a new way: unlike other common drugs targeting this pathway (eg tadalafil and sildenafil), riociguat acts independently of endogenous NO. This MiniReview focuses on PAH treatment with riociguat and on its advantages and disadvantages compared with other drugs targeting the NO pathway. In the PATENT-1 trial (NCT00810693), riociguat improved significantly the 6-minute walking distance in patients suffering from PAH, with a mean difference (MD) of 36 m compared with a placebo group. The results are comparable to those found for its competitors tadalafil (MD of 33 m) and sildenafil (MD of 50 m) in the PHIRST-1 trial (NCT00125918) and the SUPER-1 trial (NCT00644605). No obvious advantages were found regarding pharmacokinetic features and adverse events. In the RESPITE study (NCT02007629), patients with PAH with insufficient response to treatment with tadalafil or sildenafil were switched to riociguat. These results indicate that riociguat might be superior regarding efficacy to PDE-5 inhibitors in a patient group, where endogenous NO production might be insufficient. This finding was further examined in the REPLACE study (NCT02891850). Moreover, riociguat has shown promising anti-proliferative, anti-inflammatory and anti-fibrotic effects in animal models. Further investigations are needed to determine whether this applies also to human beings. Taken together, riociguat induces vasodilation of the pulmonary arteries and leads to an improvement in the ability to carry out physical activity.


Assuntos
Ativadores de Enzimas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Substituição de Medicamentos , Endotelinas/metabolismo , Ativadores de Enzimas/uso terapêutico , Epoprostenol/metabolismo , Guanilato Ciclase/metabolismo , Humanos , Óxido Nítrico/metabolismo , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Vasodilatação/efeitos dos fármacos
20.
J Vasc Res ; 56(4): 204-214, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31189158

RESUMO

The reduced expression and function of voltage-dependent potassium (KV) channels have been involved in the pathogenesis of hypoxia-induced pulmonary hypertension (HPH), leading to pulmonary vasoconstriction and vascular remodeling, while the upregulation of KV channels is of therapeutic significance for pulmonary hypertension. Beraprost sodium (BPS) has been shown to be effective in patients with pulmonary hypertension. However, the effect of BPS on O2-sensitive KV channels in pulmonary artery smooth muscle cells (PASMCs) remains unclear. In the present study, the effect of BPS on rats with HPH was observed, and the influence of BPS on the expression and function of O2-sensitive KV channels in PASMCs was investigated. The results revealed that BPS reduced mean pulmonary artery pressure, suppressed right ventricular hypertrophy, and attenuated the remodeling of pulmonary arteries in rats exposed to discontinuous hypoxia for 4 weeks (8 h/day). This was accompanied with the significantly upregulated expression of KV channel α-subunits (KV1.2, KV1.5 and KV2.1) and O2-sensitive voltage-gated K+ (KV) channel current (IK(V)) in small pulmonary arteries in HPH model rats, as well as in hypoxia-induced PASMCs. Furthermore, in vitrostudies have revealed that the upregulation of BPS on O2-sensitive KV channels was significantly inhibited after treatment with prostaglandin E2 receptor subtype EP4 antagonist GW627368X. Taken together, these results suggest that BPS attenuates the development of HPH through the upregulation of O2-sensitive KV channels, which was probably via the EP4 receptor-related pathway.


Assuntos
Anti-Hipertensivos/farmacologia , Epoprostenol/análogos & derivados , Hipóxia/complicações , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Receptores de Prostaglandina E Subtipo EP4/agonistas , Vasodilatadores/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Epoprostenol/farmacologia , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/metabolismo , Oxigênio/metabolismo , /fisiopatologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Transdução de Sinais , Regulação para Cima , Remodelação Vascular/efeitos dos fármacos , Função Ventricular Direita/efeitos dos fármacos
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