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1.
J Biochem Mol Toxicol ; 33(8): e22353, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31407471

RESUMO

For 22 days after monocrotaline injection two groups of rats received either of the monocarbonyl curcumin analogs (2E,6E)-2,6-bis(2-bromobenzylidene)cycloxehanone (B2BrBC) and (2E,6E)-2,6-bis([2-trifluoromethyl]benzylidene)cyclohexanone (C66), and their right ventricle parameters were compared to those from the control and the monocrotaline injected animals. B2BrBC and C66 treatments did not prevent the monocrotaline-induced right ventricular hypertrophy but attenuated the changes in antioxidant enzyme activities and reduced inflammation. The level of thiol-based nonenzymatic antioxidants did not change in the function of monocrotaline or curcumin analogs treatment. However, due to its stronger antioxidant properties, only B2BrBC treatment was effective in the reduction of monocrotaline-associated lipid peroxidation. The obtained results suggest that increasing the levels of antioxidant enzymes may not be sufficient to reduce oxidative stress and chronic inflammation optimally and our current study supports the potential of compounds with more than one beneficial biological activity as a promising treatment against the progression of cardiac hypertrophy.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Cardiomegalia/induzido quimicamente , Curcumina/análogos & derivados , Curcumina/farmacologia , Monocrotalina/toxicidade , Animais , Cardiomegalia/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
2.
Nat Commun ; 10(1): 3551, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391533

RESUMO

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease of cardiopulmonary units. No cure is currently available due to an incomplete understanding of vascular remodeling. Here we identify CD146-hypoxia-inducible transcription factor 1 alpha (HIF-1α) cross-regulation as a key determinant in vascular remodeling and PAH pathogenesis. CD146 is markedly upregulated in pulmonary artery smooth muscle cells (PASMCs/SMCs) and in proportion to disease severity. CD146 expression and HIF-1α transcriptional program reinforce each other to physiologically enable PASMCs to adopt a more synthetic phenotype. Disruption of CD146-HIF-1α cross-talk by genetic ablation of Cd146 in SMCs mitigates pulmonary vascular remodeling in chronic hypoxic mice. Strikingly, targeting of this axis with anti-CD146 antibodies alleviates established pulmonary hypertension (PH) and enhances cardiac function in two rodent models. This study provides mechanistic insights into hypoxic reprogramming that permits vascular remodeling, and thus provides proof of concept for anti-remodeling therapy for PAH through direct modulation of CD146-HIF-1α cross-regulation.


Assuntos
Retroalimentação Fisiológica , Hipertensão Pulmonar/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Remodelação Vascular , Animais , Antígeno CD146/genética , Antígeno CD146/metabolismo , Hipóxia Celular , Células Cultivadas , Modelos Animais de Doenças , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Camundongos , Camundongos Knockout , Monocrotalina/toxicidade , Músculo Liso Vascular/citologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Cultura Primária de Células , Artéria Pulmonar/citologia , Artéria Pulmonar/patologia , Ratos , Índice de Gravidade de Doença , Regulação para Cima
3.
Chem Biol Interact ; 311: 108749, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31325423

RESUMO

PURPOSE: Excessive proliferation, migration and anti-apoptosis of pulmonary artery smooth muscle cells (PASMCs) are the basis for the development of pulmonary vascular remodeling, and it is the driving force for pulmonary arterial hypertension (PAH). 18ß-glycyrrhetinic acid (18ß-GA) is the main active substance extracted from Chinese herbal medicine licorice, with outstanding anti-inflammatory, anti-oxidation and anti-proliferative effects. Our team found in previous studies that 18ß-GA has protective effects on monocrotaline-induced PAH in rats. However, the anti-angiogenic effect of 18ß-GA on PAH remains unclear. Therefore, in order to further investigate whether the beneficial effects of 18ß-GA on PAH are related to its antiproliferative effect, we conducted experiments in vivo and in vitro. METHODS AND RESULTS: In vivo, 18ß-GA relieved mean pulmonary arterial pressure, right ventricular systolic pressure, and right ventricular hypertrophy index, improving pulmonary remodeling. In vitro, 18ß-GA significantly inhibited PDGF-BB-induced proliferation and DNA synthesis of HPASMCs, blocking the progression of G0/G1 to S phase of the cell cycle. Furthermore, after treatment with 18ß-GA, the expression of Rho A, ROCK1, ROCK2 was decreased and ROCK activity was inhibited in HPASMC. In addition, 18ß-GA also attenuated PDGF-induced changes in p27kip1, Bax and Bcl-2. CONCLUSIONS: In summary, these results indicate that 18ß-GA regulates the activity of RhoA-ROCK signaling pathway, inhibits the proliferation of HPASMCs, and has potential value in the treatment of PAH.


Assuntos
Ácido Glicirretínico/análogos & derivados , Hipertensão Pulmonar/patologia , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glicirretínico/farmacologia , Ácido Glicirretínico/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Masculino , Monocrotalina/toxicidade , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Substâncias Protetoras/uso terapêutico , Proteína Fosfatase 1/genética , Proteína Fosfatase 1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Remodelação Vascular/efeitos dos fármacos , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
4.
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
5.
Nat Commun ; 10(1): 2204, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101827

RESUMO

Pulmonary arterial hypertension (PAH) is a devastating disease with poor prognosis and limited therapeutic options. We screened for pathways that may be responsible for the abnormal phenotype of pulmonary arterial smooth muscle cells (PASMCs), a major contributor of PAH pathobiology, and identified cyclin-dependent kinases (CDKs) as overactivated kinases in specimens derived from patients with idiopathic PAH. This increased CDK activity is confirmed at the level of mRNA and protein expression in human and experimental PAH, respectively. Specific CDK inhibition by dinaciclib and palbociclib decreases PASMC proliferation via cell cycle arrest and interference with the downstream CDK-Rb (retinoblastoma protein)-E2F signaling pathway. In two experimental models of PAH (i.e., monocrotaline and Su5416/hypoxia treated rats) palbociclib reverses the elevated right ventricular systolic pressure, reduces right heart hypertrophy, restores the cardiac index, and reduces pulmonary vascular remodeling. These results demonstrate that inhibition of CDKs by palbociclib may be a therapeutic strategy in PAH.


Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Animais , Linhagem Celular , Quinases Ciclina-Dependentes/metabolismo , Modelos Animais de Doenças , Hipertensão Pulmonar Primária Familiar/induzido quimicamente , Hipertensão Pulmonar Primária Familiar/patologia , Hipertensão Pulmonar Primária Familiar/cirurgia , Humanos , Indóis/toxicidade , Pulmão/irrigação sanguínea , Pulmão/patologia , Pulmão/cirurgia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monocrotalina/toxicidade , Músculo Liso Vascular/citologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Artéria Pulmonar/citologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Piridinas/uso terapêutico , Pirróis/toxicidade , Ratos , Ratos Endogâmicos WKY , Ratos Sprague-Dawley , Resultado do Tratamento
6.
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
7.
PLoS One ; 14(4): e0214740, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30964911

RESUMO

Pulmonary hypertension (PH) increases the work of the right ventricle (RV) and causes right-sided heart failure. This study examined RV mitochondrial function and ADP transfer in PH animals advancing to right heart failure, and investigated a potential therapy with the specific ß1-adrenergic-blocker metoprolol. Adult Wistar rats (317 ± 4 g) were injected either with monocrotaline (MCT, 60 mg kg-1) to induce PH, or with an equivalent volume of saline for controls (CON). At three weeks post-injection the MCT rats began oral metoprolol (10 mg kg-1 day-1-) or placebo treatment until heart failure was observed in the MCT group. Mitochondrial function was then measured using high-resolution respirometry from permeabilised RV fibres. Relative to controls, MCT animals had impaired mitochondrial function but maintained coupling between myofibrillar ATPases and mitochondria, despite an increase in ADP diffusion distances. Cardiomyocytes from the RV of MCT rats were enlarged, primarily due to an increase in myofibrillar protein. The ratio of mitochondria per myofilament area was decreased in both MCT groups (p ≤ 0.05) in comparison to control (CON: 1.03 ± 0.04; MCT: 0.74 ± 0.04; MCT + BB: 0.74 ± 0.03). This not only implicates impaired energy production in PH, but also increases the diffusion distance for metabolites within the MCT cardiomyocytes, adding an additional hindrance to energy supply. Together, these changes may limit energy supply in MCT rat hearts, particularly at high cardiac workloads. Metoprolol treatment did not delay the onset of heart failure symptoms, improve mitochondrial function, or regress RV hypertrophy.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Metoprolol/farmacologia , Mitocôndrias/efeitos dos fármacos , Função Ventricular Direita/efeitos dos fármacos , Adenosina Trifosfatases/metabolismo , Administração Oral , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Animais , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/prevenção & controle , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Masculino , Metoprolol/uso terapêutico , Mitocôndrias/metabolismo , Monocrotalina/toxicidade , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miofibrilas/metabolismo , Miofibrilas/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Efeito Placebo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
8.
Mol Med Rep ; 19(5): 3823-3830, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896881

RESUMO

Pulmonary arterial hypertension (PAH) is a severe and progressive disease characterized by the remodeling of small pulmonary arteries. The aberrant proliferation of pulmonary arterial smooth muscle cells (PASMCs) is the primary feature of PAH. MicroRNA (miR)­132 has been demonstrated to inhibit the proliferation of vascular smooth muscle cells and repress neointimal formation. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a direct target of miR­132 that has been revealed to be involved in the development of PAH. However, the role of miR­132 in PAH remains unclear. The present study demonstrated that miR­132 expression was upregulated in monocrotaline­induced PAH rats and platelet­derived growth factor­induced PASMCs. In addition, treatment of PASMCs with miR­132 mimics inhibited their proliferation, whereas miR­132 inhibition exhibited the opposite effects. Furthermore, miR­132 mimics promoted cell migration and maintained the PASMC contractile phenotype. Finally, the expression levels of PTEN were significantly decreased in PAH and PASMCs treated with miR­132 mimics. Taken collectively, the data suggested that miR­132 regulated PASMC function via PTEN and that it may be used as a potential target for the treatment of PAH.


Assuntos
Movimento Celular , Proliferação de Células , Hipertensão Pulmonar/patologia , MicroRNAs/genética , Músculo Liso Vascular/patologia , PTEN Fosfo-Hidrolase/metabolismo , Artéria Pulmonar/patologia , Animais , Apoptose , Células Cultivadas , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Masculino , Monocrotalina/toxicidade , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , PTEN Fosfo-Hidrolase/genética , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
9.
Biosci Biotechnol Biochem ; 83(6): 1000-1010, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30835622

RESUMO

Pulmonary hypertension (PH) is a life-threatening lung disease. PH with concomitant lung diseases, e.g., idiopathic pulmonary fibrosis, is associated with poor prognosis. Development of novel therapeutic vasodilators for treatment of these patients is a key imperative. We evaluated the efficacy of dual activation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) using an active, small-molecule phosphodiesterase (PDE4)/PDE5 dual inhibitor (Compound A). Compound A increased both cAMP and cGMP levels in WI-38 lung fibroblasts and suppressed the expressions of type-1 collagen α1 chain and fibronectin. Additionally, compound A reduced right ventricular weight/left ventricular weight+septal weight ratio, brain natriuretic peptide expression levels in right ventricle, C─C motif chemokine ligand 2 expression levels in lung, and plasma surfactant protein D. Our data indicate that dual activation of cAMP/cGMP pathways may be a novel treatment strategy for PH.


Assuntos
AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Inflamação/terapia , Pulmão/efeitos dos fármacos , Monocrotalina/toxicidade , Inibidores da Fosfodiesterase 5/uso terapêutico , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Células Cultivadas , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Epitélio/lesões , Fibronectinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Humanos , Pulmão/metabolismo , Pulmão/patologia , Inibidores da Fosfodiesterase 5/farmacologia , Ratos Wistar , Fator de Crescimento Transformador beta/fisiologia
10.
Phytomedicine ; 58: 152867, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30844585

RESUMO

BACKGROUND: Toosendan Fructus is traditionally used as an insecticide or digestive tract parasiticide for treating digestive parasites in China. It is recorded to have little toxicity in Chinese Pharmacopoeia and has been found to cause severe liver injury during clinical practice. PURPOSE: This study aims to identify candidate serum microRNAs (miRNAs) as potential toxicological biomarkers for reflecting the hepatotoxicity induced by toosendanin (TSN), which is the main toxic compound isolated from Toosendan Fructus METHODS: Alanine/aspartate aminotransferase (ALT/AST) activities detection and liver histological observation were performed to evaluate the liver injury induced by TSN or other hepatotoxicants in mice. miRNAs chip analysis and Real-time PCR assay were conducted to identify the altered miRNAs in serum from TSN-treated mice RESULTS: The results of serum ALT/AST and liver histological evaluation showed that TSN (10 mg/kg) induced hepatotoxicity in mice. The results of miRNAs chip showed that the expression of 81 serum miRNAs was obviously altered in mice treated with TSN for 12 h, and 22 of them have passed the further validation in serum from mice treated with TSN for both 6 h and 12 h. These 22 miRNAs were supposed to be the candidate toxicological biomarkers for TSN-induced hepatotoxicity with more sensitivity as compared to the alteration of AST or ALT activity. Moreover, the expression of miRNA-122-3p and mcmv-miRNA-m01-4-3p was not only increased in TSN-treated mice, but also increased in mice treated with other hepatotoxicants including acetaminophen (APAP), monocrotaline (MCT) and diosbuibin B (DB). Only the expression of serum miRNA-367-3p was increased in TSN-treated mice but not changed in the liver injury induced by APAP, MCT or DB CONCLUSION: miR-122-3p and mcmv-miRNA-m01-4-3p may be two commonly sensitive biomarkers for reflecting the hepatotoxicity induced by exogenous hepatotoxicants, and miR-367-3p may be a specific biomarker for reflecting the liver injury induced by TSN.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/sangue , Medicamentos de Ervas Chinesas/toxicidade , Medicina Tradicional Chinesa/efeitos adversos , MicroRNAs/sangue , Acetaminofen/toxicidade , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Biomarcadores/sangue , Compostos Heterocíclicos de 4 ou mais Anéis/toxicidade , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monocrotalina/toxicidade , Distribuição Aleatória , Organismos Livres de Patógenos Específicos
11.
Arterioscler Thromb Vasc Biol ; 39(4): 704-718, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30816802

RESUMO

Objective- Pulmonary arterial hypertension is characterized by progressive pulmonary vascular remodeling and persistently elevated mean pulmonary artery pressures and pulmonary vascular resistance. We aimed to investigate whether transthoracic pulmonary artery denervation (TPADN) attenuated pulmonary artery (PA) remodeling, improved right ventricular (RV) function, and affected underlying mechanisms. We also explored the distributions of sympathetic nerves (SNs) around human PAs for clinical translation. Approach and Results- We identified numerous SNs in adipose and connective tissues around the main PA trunks and bifurcations in male Sprague Dawley rats, which were verified in samples from human heart transplant patients. Pulmonary arterial hypertensive rats were randomized into TPADN and sham groups. In the TPADN group, SNs around the PA trunk and bifurcation were completely and accurately removed under direct visualization. The sham group underwent thoracotomy. Hemodynamics, RV function, and pathological changes in PA and RV tissues were measured via right heart catheterization, cardiac magnetic resonance imaging, and pathological staining, respectively. Compared with the sham group, the TPADN group had lower mean pulmonary arterial pressures, less PA and RV remodeling, and improved RV function. Furthermore, TPADN inhibited neurohormonal overactivation of the sympathetic nervous system and renin-angiotensin-aldosterone system and regulated abnormal expressions and signaling of neurohormone receptors in local tissues. Conclusions- There are numerous SNs around the rat and human main PA trunks and bifurcations. TPADN completely and accurately removed the main SNs around PAs and attenuated pulmonary arterial hypertensive progression by inhibiting excessive activation of the sympathetic nervous system and renin-angiotensin-aldosterone system neurohormone-receptor axes.


Assuntos
/cirurgia , Simpatectomia/métodos , Adolescente , Aldosterona/fisiologia , Animais , Pré-Escolar , Citocinas/sangue , Progressão da Doença , Feminino , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipertrofia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Monocrotalina/toxicidade , Neurotransmissores/fisiologia , Estresse Oxidativo , /fisiopatologia , Artéria Pulmonar/inervação , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores de Neurotransmissores/biossíntese , Receptores de Neurotransmissores/genética , Receptores de Neurotransmissores/fisiologia , Sistema Renina-Angiotensina/fisiologia , Sistema Nervoso Simpático/anatomia & histologia
12.
Nutrients ; 11(3)2019 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-30857304

RESUMO

Polyphenols present in some alcoholic beverages have been linked to beneficial effects in preventing cardiovascular diseases. Polyphenols found in beer with anti-proliferative and anti-cancer properties are appealing in the context of the quasi-malignant phenotype of pulmonary arterial hypertension (PAH). Our purpose was to evaluate if the chronic ingestion of a xanthohumol-fortified beer (FB) would be able to modulate the pathophysiology of experimental PAH. Male Wistar rats with monocrotaline (MCT)-induced PAH (60 mg/kg) were allowed to drink either xanthohumol-fortified beer (MCT + FB) or 5.2% ethanol (MCT + SHAM) for a period 4 weeks. At the end of the protocol, cardiopulmonary exercise testing and hemodynamic recordings were performed, followed by sample collection for further analysis. FB intake resulted in a significant attenuation of the pulmonary vascular remodeling in MCT + FB animals. This improvement was paralleled with the downregulation in expression of proteins responsible for proliferation (ERK1/2), cell viability (AKT), and apoptosis (BCL-XL). Moreover, MCT + FB animals presented improved right ventricle (RV) function and remodeling accompanied by VEGFR-2 pathway downregulation. The present study demonstrates that a regular consumption of xanthohumol through FB modulates major remodeling pathways activated in experimental PAH.


Assuntos
Cerveja/análise , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Flavonoides/administração & dosagem , Hipertensão Pulmonar/induzido quimicamente , Propiofenonas/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Remodelação Vascular/efeitos dos fármacos , Animais , MAP Quinases Reguladas por Sinal Extracelular/genética , Flavonoides/química , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hipertensão Pulmonar/patologia , Masculino , Monocrotalina/toxicidade , Propiofenonas/química , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Wistar
13.
Reprod Toxicol ; 85: 34-41, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30771476

RESUMO

Hepatic and pulmonary toxicity in fetal rats induced by pyrrolizidine alkaloids (PAs) was investigated. Retrorsine (RTS) or monocrotaline (MCT) was intragastrically administered during pregnancy. The reduction of body and tail lengths was consistent with body weight loss in PA-exposed fetuses, and pathological lesions in liver and lung were observed only in fetuses. Both PAs reduced fetal serum transaminase activities. The GSH/GSSG ratio, GSH peroxidase and superoxide dismutase activities also decreased but glutathione S-transferase activity increased in fetal lung, especially for MCT. The pyrrole-protein adducts in fetal liver and lung could be detected, and those adducts in RTS fetal lungs were about 65% of those in MCT group. In conclusion, prenatal PAs exposure induced fetal hepatic and pulmonary toxicities through the generation of pyrrole metabolites and oxidative injury. The difference on fetal pulmonary redox homeostasis between two PAs groups might be associated with the content of PAs migrated to fetal lungs.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Feto/efeitos dos fármacos , Lesão Pulmonar/induzido quimicamente , Monocrotalina/toxicidade , Lesões Pré-Natais/induzido quimicamente , Alcaloides de Pirrolizidina/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Feminino , Retardo do Crescimento Fetal/induzido quimicamente , Fígado/efeitos dos fármacos , Fígado/embriologia , Fígado/metabolismo , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/embriologia , Pulmão/patologia , Lesão Pulmonar/patologia , Troca Materno-Fetal , Gravidez , Lesões Pré-Natais/metabolismo , Lesões Pré-Natais/patologia , Ratos Wistar
14.
J Endocrinol Invest ; 42(8): 951-965, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30674010

RESUMO

BACKGROUND: Activation of the farnesoid X receptor (FXR), a member of the nuclear receptor steroid superfamily, leads to anti-inflammatory and anti-fibrotic effects in several tissues, including the lung. We have recently demonstrated a protective effect of the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) in rat models of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and bleomycin-induced pulmonary fibrosis. The aim of the present study was to investigate whether the positive effects of OCA treatment could be exerted also in established MCT-induced PAH, i.e., starting treatment 2 weeks after MCT administration. METHODS: Rats with MCT-induced PAH were treated, 2 weeks after MCT administration, with OCA or tadalafil for two additional weeks. Pulmonary functional tests were performed at week 2 (before treatment) and four (end of treatment). At the same time points, lung morphological features and expression profile of genes related to smooth muscle relaxation/contraction and tissue remodeling were also assessed. RESULTS: 2 weeks after MCT-induced injury, the treadmill resistance (a functional parameter related to pulmonary hypertension) was significantly decreased. At the same time point, we observed right ventricular hypertrophy and vascular remodeling, with upregulation of genes related to inflammation. At week 4, we observed a further worsening of the functional and morphological parameters, accompanied by dysregulation of inflammatory and extracellular matrix markers mRNA expression. Administration of OCA (3 or 10 mg/kg/day), starting 2 weeks after MCT-induced injury, significantly improved pulmonary function, effectively normalizing the exercise capacity. OCA also reverted most of the lung alterations, with a significant reduction of lung vascular wall thickness, right ventricular hypertrophy, and restoration of the local balance between relaxant and contractile pathways. Markers of remodeling pathways were also normalized by OCA treatment. Notably, results with OCA treatment were similar, or even superior, to those obtained with tadalafil, a recently approved treatment for pulmonary hypertension. CONCLUSIONS: The results of this study demonstrate a significant therapeutic effect of OCA in established MCT-induced PAH, improving exercise capacity associated with reduction of right ventricular hypertrophy and lung vascular remodeling. Thus, OCA dosing in a therapeutic protocol restores the balance between relaxant and contractile pathways in the lung, promoting cardiopulmonary protective actions in MCT-induced PAH.


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Modelos Animais de Doenças , Hipertensão Pulmonar/tratamento farmacológico , Monocrotalina/toxicidade , Fibrose Pulmonar/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Antibióticos Antineoplásicos/toxicidade , Bleomicina/toxicidade , Ácido Quenodesoxicólico/farmacologia , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/patologia , Masculino , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Ratos , Ratos Sprague-Dawley
15.
Arterioscler Thromb Vasc Biol ; 39(4): e130-e145, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30676070

RESUMO

Objective- Macrophages participate in the pathogenesis of pulmonary arterial hypertension (PAH). Lgmn (Legumain), a newly discovered cysteine proteinase belonging to the C13 peptidase family, is primarily expressed in macrophages; however, its roles in PAH remain unknown. Approach and Results- Herein, Lgmn was upregulated in lung tissues of PAH mice subjected to hypoxia plus SU5416 and PAH rats challenged with monocrotaline. Global Lgmn ablation and macrophage-specific ablation alleviated PAH compared with wild-type mice, evident from a reduction in right ventricular systolic pressure, the ratio of the right ventricular wall to the left ventricular wall plus the septum, the pulmonary vascular media thickness, and pulmonary vascular muscularization. Increased expression of ECM (extracellular matrix) proteins was correlated with MMP (matrix metalloproteinase)-2 activation and TGF (transforming growth factor)-ß1 signaling in the PAs. Although Lgmn did not affect inflammatory cell infiltration and PA smooth muscle cell proliferation, it drove increased the synthesis of ECM proteins via MMP-2 activation. MMP-2 hydrolyzed the TGF-ß1 precursor to the active form. An Lgmn-specific inhibitor markedly ameliorated PAH. Clinically, serum Lgmn levels were closely associated with the severity of idiopathic PAH. Conclusions- Our results indicate that Lgmn inhibition could be an effective strategy for preventing or delaying PAH.


Assuntos
Cisteína Endopeptidases/fisiologia , Hipertensão Pulmonar/enzimologia , Macrófagos/enzimologia , Metaloproteinase 2 da Matriz/fisiologia , Fator de Crescimento Transformador beta1/fisiologia , Animais , Inibidores de Caspase/farmacologia , Cisteína Endopeptidases/deficiência , Proteínas da Matriz Extracelular/metabolismo , Feminino , Seguimentos , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/prevenção & controle , Hipóxia/enzimologia , Indóis/toxicidade , Inflamação , Pulmão/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Monocrotalina/toxicidade , Pirróis/toxicidade , Ratos , Índice de Gravidade de Doença , Transdução de Sinais , Remodelação Vascular/fisiologia
16.
Heart Vessels ; 34(3): 545-555, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30386918

RESUMO

Fatty acid (FA) oxidation is impaired and glycolysis is promoted in the damaged heart. However, the factor(s) in the early stages of myocardial metabolic impairment remain(s) unclear. C57B6 mice were subcutaneously administered monocrotaline (MCT) in doses of 0.3 mg/g body weight twice a week for 3 or 6 weeks. Right and left ventricles at 3 and 6 weeks after administration were subjected to capillary electrophoresis-mass spectrometry metabolomic analysis. We also examined mRNA and protein levels of key metabolic molecules. Although no evidence of PH and right ventricular failure was found in the MCT-administered mice by echocardiographic and histological analyzes, the expression levels of stress markers such as TNFα and IL-6 were increased in right and left ventricles even at 3 weeks, suggesting that there was myocardial damage. Metabolites in the tricarboxylic acid (TCA) cycle were decreased and those in glycolysis were increased at 6 weeks. The expression levels of FA oxidation-related factors were decreased at 6 weeks. The phosphorylation level of pyruvate dehydrogenase (PDH) was significantly decreased at 3 weeks. FA oxidation and the TCA cycle were down-regulated, whereas glycolysis was partially up-regulated by MCT-induced myocardial damage. PDH activation preceded these alterations, suggesting that PDH activation is one of the earliest events to compensate for a subtle metabolic impairment from myocardial damage.


Assuntos
Cardiomiopatias/metabolismo , Regulação para Baixo , Ácidos Graxos/metabolismo , Ventrículos do Coração/metabolismo , Miocárdio/metabolismo , Complexo Piruvato Desidrogenase/metabolismo , Animais , Western Blotting , Cardiomiopatias/induzido quimicamente , Modelos Animais de Doenças , Ventrículos do Coração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monocrotalina/toxicidade , Miocárdio/patologia , Oxirredução
17.
Respir Res ; 19(1): 254, 2018 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-30547791

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is related to inflammation, and the lncRNA H19 is associated with inflammation. However, whether PDGF-BB-H19-let-7b-AT1R axis contributes to the pathogenesis of PAH has not been thoroughly elucidated to date. This study investigated the role of H19 in PAH and its related mechanism. METHODS: In the present study, SD rats, C57/BL6 mice and H19-/- mice were injected with monocrotaline (MCT) to establish a PAH model. H19 was detected in the cytokine-stimulated pulmonary arterial smooth muscle cells (PASMCs), serum and lungs of rats/mice. H19 overexpression and knockdown experiments were also conducted. A dual luciferase reporter assay was used to explore whether let-7b is a sponge miRNA of H19, and AT1R is a novel target of let-7b. A CCK-8 assay and flow cytometry were used to analyse cell proliferation. RESULTS: The results showed that H19 was highly expressed in the serum and lungs of MCT-induced rats/mice, and H19 was upregulated by PDGF-BB in vitro. H19 upregulated AT1R expression via sponging miRNA let-7b following PDGF-BB stimulation. AT1R is a novel target of let-7b. Moreover, the overexpression of H19 and AT1R could facilitate PASMCs proliferation in vitro. H19 knockout protected mice from pulmonary artery remodeling and PAH following MCT treatment. CONCLUSION: Our study showed that H19 is highly expressed in MCT-induced rodent lungs and upregulated by PDGF-BB. The H19-let-7b-AT1R axis contributed to the pathogenesis of PAH by stimulating PASMCs proliferation. The H19 knockout had a protective role in the development of PAH. H19 may be a potential tar-get for the treatment of PAH.


Assuntos
Hipertensão Pulmonar/metabolismo , MicroRNAs/biossíntese , Monocrotalina/toxicidade , Miócitos de Músculo Liso/metabolismo , RNA Longo não Codificante/biossíntese , Receptores de Angiotensina/biossíntese , Indutores da Angiogênese/farmacologia , Animais , Becaplermina/farmacologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Hipertensão Pulmonar/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/efeitos dos fármacos , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , RNA Longo não Codificante/agonistas , Ratos , Ratos Sprague-Dawley
18.
Int J Mol Sci ; 20(1)2018 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-30586863

RESUMO

Pulmonary arterial hypertension (PAH) leads to lethal right ventricular failure (RVF). Periostin (POSTN) mRNA expression is increased in right ventricles (RVs) of monocrotaline (MCT)-induced PAH model rats. However, the pathophysiological role of POSTN in RVF has not been clarified. We investigated the effects of POSTN on inducible nitric oxide (NO) synthase (iNOS) expression and NO production, which causes cardiac dysfunction, in right ventricular fibroblasts (RVFbs). Male Wistar rats were intraperitoneally injected with MCT (60 mg/kg) or saline. Three weeks after injection, RVFbs were isolated from RVs of MCT- or saline-injected rats (MCT-RVFb or CONT-RVFb). In MCT-RVFb, iNOS expression and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) were higher than those in CONT-RVFb. Recombinant POSTN increased iNOS expression and NO production, which were prevented by a pharmacological inhibition of ERK1/2, JNK or NF-κB in RVFbs isolated from normal rats. Culture medium of POSTN-stimulated RVFbs suppressed Ca2+ inflow through l-type Ca2+ channel (LTCC) in H9c2 cardiomyoblasts. We demonstrated that POSTN enhances iNOS expression and subsequent NO production via ERK1/2, JNK, and NF-κB signaling pathways in RVFbs. POSTN might mediate RVF through the suppression of LTCC activity of cardiomyocytes by producing NO from RVFbs in PAH model rats.


Assuntos
Moléculas de Adesão Celular/metabolismo , Hipertensão Pulmonar/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Moléculas de Adesão Celular/genética , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Ventrículos do Coração/citologia , Hipertensão Pulmonar/induzido quimicamente , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Monocrotalina/toxicidade , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
19.
Phytomedicine ; 50: 157-165, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30466974

RESUMO

BACKGROUND: Extract of the wild orchid, Eulophia macrobulbon (EM) inhibits phosphodiesterase5 (PDE5) suggesting it could preferentially dilate the pulmonary vasculature. PURPOSE AND STUDY DESIGN: To pharmacologically characterize the vascular actions of EM ethanolic extract and its active compound, 1-(4'-hydroxybenzyl)-4,8-dimethoxyphenanthrene-2,7-diol using isolated pulmonary arteries (PA) from rats having pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). PA were fixed and prepared for histology. RESULTS: EM extract relaxed PA (EC50 = 0.17  mg/ml, Emax ∼ 94%) but less so for aorta (EC50 = 0.51 mg/ml, Emax ∼ 62%), suggesting some selectivity towards the pulmonary circulation. PA vasorelaxation was reduced by endothelial removal or NG-nitro-L-arginine methyl ester, but unaffected by indomethacin, apamin +charybdotoxin, 4-aminopyridine, glibenclamide, iberiotoxin, or 1H - [1,2,4]oxadiazolo[4,3-a]quinoxalin -1- one. Sodium nitroprusside-induced relaxation was enhanced by EM extract, probably via PDE5 inhibition. EM extract reduced contractions evoked by extracellular Ca2+application, and inhibited intracellular Ca2+release activated by phenylephrine. The phenanthrene relaxed PA independently of the endothelium. MCT thickened walls and decreased lumens of PA, and hypertrophied right ventricular myocytes, effects ameliorated by 3 weeks of oral sildenafil (20  mg/kg) or EM extract (15, 450 or 1000  mg/kg). CONCLUSION: PAH is improved by EM extract acting through PA relaxation mediated through endothelial NO, reduced Ca2+-mobilization, and reduced PA wall thickness and right ventricular hypertrophy.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Orchidaceae/química , Extratos Vegetais/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Cálcio/metabolismo , Endotélio Vascular/efeitos dos fármacos , Hipertensão Pulmonar/induzido quimicamente , Hipertrofia Ventricular Direita/tratamento farmacológico , Técnicas In Vitro , Masculino , Monocrotalina/toxicidade , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Nitroprussiato/farmacologia , Tubérculos/química , Ratos , Ratos Sprague-Dawley , Tailândia
20.
Biomed Res Int ; 2018: 4892349, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30320134

RESUMO

Purpose: This study aimed to explore whether bone marrow- (BM-) derived endothelial progenitor cells (EPCs) contributing to monocrotaline- (MCT-) induced pulmonary arterial hypertension (PAH) in rats via modulating store-operated Ca2+ channels (SOC). Methods: Sprague Dawley (SD) rats were assigned into MCT group (n = 30) and control group (n = 20). Rats in MCT group were subcutaneously administered with 60 mg/kg MCT solution, and rats in control group were injected with equal amount of vehicle. After 3 weeks of treatment, right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) of two groups were measured, and BM-derived EPCs were isolated. Immunochemistry identification and vasculogenesis detection of EPCs were then performed. [Ca2+]cyt measurement was performed to detect store-operated calcium entry (SOCE) in two groups, followed by determination of Orai and canonical transient receptor potential (TRPC) channels expression. Results: After 3 weeks of treatment, there were significant increases in RVSP and RVHI in MCT group compared with control group, indicating that MCT successfully induced PAH in rats. Moreover, the SOCE ([Ca2+]cyt rise) in BM-derived EPCs of MCT group was lower than that of control group. Furthermore, the expression levels of Orai3, TRPC1, TRPC3, and TRPC6 in BM-derived EPCs were decreased in MCT group in comparison with control group. Conclusions: The SOC activities were inhibited in BM-derived EPCs of MCT-treated rats. These results may be associated with the depressed expression of Orai3, TRPC1, TRPC3, and TRPC6, which are major mediators of SOC.


Assuntos
Células da Medula Óssea/metabolismo , Canais de Cálcio/biossíntese , Células Progenitoras Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertensão Pulmonar , Monocrotalina/toxicidade , Animais , Células da Medula Óssea/patologia , Células Progenitoras Endoteliais/patologia , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Ratos , Ratos Sprague-Dawley
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