RESUMO
BACKGROUND: The evidence regarding the association of reproductive factors with cardiovascular diseases (CVDs) is limited. AIMS: To investigate the relationship of reproductive factors with the risk of CVDs, as well as all-cause and cardiovascular mortality. METHODS: This study included 16,404 adults with reproductive factors from the National Health and Nutrition Examination Survey (NHANES) and followed up until 31 December 2019. Logistic models and restricted cubic spline models were used to assess the association of reproductive factors with CVDs. COX proportional hazards models and restricted cubic spline models, with adjustment for potential confounding, were employed to analyze the relation between reproductive factors and cardiovascular and all-cause death. RESULTS: There is a nonlinear relationship between age at menarche and CVDs. Age at menopause ≤ 11(OR 1.36, 95% CI 1.10-1.69) was associated with an increased risk of CVDs compared to ages 12-13 years. Age at Menopause ≤ 44 (OR 1.69, 95% CI 1.40-2.03) was associated with increased CVDs compared to age 35-49 years. Number of pregnancies ≥ 5(OR 1.26, 95% CI 1.02-1.55) was associated with an increased risk of CVDs compared to one pregnancy. In continuous variable COX regression models, a later age at menopause (HR 0.98, 95% CI 0.97-0.99) and a longer reproductive lifespan (HR 0.98, 95% CI 0.97-0.99) were associated with a decreased risk of all-cause death. A later age at menopause (HR 0.98, 95% CI 0.97-0.99) and a longer reproductive lifespan (HR 0.98, 95% CI 0.97-0.99) were associated with a decreased risk of cardiac death. CONCLUSIONS: Female reproductive factors are significant risk factors for CVDs American women.
Assuntos
Doenças Cardiovasculares , Gravidez , Adulto , Feminino , Estados Unidos/epidemiologia , Humanos , Criança , Adolescente , Pessoa de Meia-Idade , Inquéritos Nutricionais , Menopausa , Reprodução , Fatores de RiscoRESUMO
Vascular dysfunction resulting from diabetes is an important factor in arteriosclerosis. Previous studies have shown that during hyperglycaemia and diabetes, AKAP150 promotes vascular tone enhancement by intensifying the remodelling of the BK channel. However, the interaction between AKAP150 and the BK channel remains open to discussion. In this study, we investigated the regulation of impaired BK channel-mediated vascular dysfunction in diabetes mellitus. Using AKAP150 null mice (AKAP150-/- ) and wild-type (WT) control mice (C57BL/6J), diabetes was induced by intraperitoneal injection of streptozotocin. We found that knockout of AKAP150 reversed vascular remodelling and fibrosis in mice with diabetes and in AKAP150-/- diabetic mice. Impaired Akt/GSK3ß signalling contributed to decreased BK-ß1 expression in aortas from diabetic mice, and the silencing of AKAP150 increased Akt phosphorylation and BK-ß1 expression in MOVAS cells treated with HG medium. The inhibition of Akt activity caused a decrease in BK-ß1 expression, and treatment with AKAP150 siRNA suppressed GSK3ß expression in the nuclei of MOVAS cells treated with HG. Knockout of AKAP150 reverses impaired BK channel-mediated vascular dysfunction through the Akt/GSK3ß signalling pathway in diabetes mellitus.
Assuntos
Proteínas de Ancoragem à Quinase A/genética , Complicações do Diabetes/genética , Diabetes Mellitus Experimental/genética , Glicogênio Sintase Quinase 3 beta/genética , Subunidades beta do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Animais , Arteriosclerose/complicações , Arteriosclerose/genética , Arteriosclerose/patologia , Arteriosclerose/terapia , Complicações do Diabetes/patologia , Complicações do Diabetes/terapia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/terapia , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Humanos , Hiperglicemia/complicações , Hiperglicemia/genética , Hiperglicemia/patologia , Hiperglicemia/terapia , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Camundongos , Camundongos Knockout , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologiaRESUMO
Pulmonary arterial hypertension (PAH) is a diffuse pulmonary microvascular remodeling disease accompanied by malignant proliferation of pulmonary artery smooth muscle cells (PASMCs), which causes persistent pulmonary artery pressure elevation, right ventricular hypertrophy (RVH) and death. However, current therapies targeting pulmonary vascular remodeling and RVH remain poorly effective in reversing PAH. Overactivation of the protein tyrosine kinase Src plays an important role in tumor cell growth, proliferation and invasion; we thus hypothesized that inhibitors targeting Src activation could reverse experimental PAH. We demonstrated that Src was markedly activated in hypoxia-stimulated PASMCs from donors and PASMCs isolated from PAH patients. We investigated the effects of the Src-selective inhibitor 1-(1,1-dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP1) and berberine (BBR) on PAH-PASMC proliferation and migration by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU) and wound-healing assays. Our in vitro results showed that inhibition of Src (Tyr416) phosphorylation repressed PAH-PASMC proliferation and migration by inhibiting hypoxia-inducible factor-1α (HIF-1α) expression through Akt/mTOR signal pathway. In vivo, PP1 and BBR significantly alleviated distal pulmonary vascular remodeling and decreased right ventricular systolic pressure (RVSP) and RVH in Sugen (SU) 5416/hypoxia (SU-PAH) mice. These findings demonstrate that pharmacological (PP1 or BBR) inhibition of Src activation could be a novel means of treating severe pulmonary vascular remodeling and RVH in PAH patients.
Assuntos
Hipertrofia Ventricular Direita/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Hipertensão Arterial Pulmonar/tratamento farmacológico , Quinases da Família src/genética , Animais , Berberina/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Hipertrofia Ventricular Direita/genética , Hipertrofia Ventricular Direita/patologia , Camundongos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/patologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Resistência Vascular/efeitos dos fármacos , Quinases da Família src/antagonistas & inibidoresRESUMO
Essential thrombocythemia (ET) can cause systemic vascular thrombosis, but the involvement of coronary arteries is rare. This study is aimed to analyze the characteristics, treatment, and prognosis during follow-up in patients with ET after percutaneous coronary intervention (PCI). A total of eight patients with ET who had coronary heart disease and treated with PCI in our hospital from 2012 to 2018 were retrospectively studied. The basic clinical information with clinical data, data of coronary intervention, application of anti-platelet and platelet reducing drugs, and the results of long-term follow-up were recorded. There were five males and three females with a median age of 67 years. Clinical presentation was unstable angina in four cases, stable angina in one case, ST-elevation myocardial infarction in two cases, and non-ST elevation myocardial infarction in one case. The average platelet count was 722 × 109/L in admission, and hydroxyurea was used in seven cases. Coronary angiography suggested that all eight cases were single-vessel lesion. All the patients received PCI treatment, and Drug-eluting stent (DES) was used in all cases. Six were treated with one stent, one was treated with two stents and one was treated with three stents. After PCI, aspirin, and clopidogrel (or ticagrelor) were used in all cases. During the follow-up, one developed stent thrombus 2 months later, two developed stent restenosis 1 year later. In conclusion, PCI is an effective method of revascularization in patients with ET; but it may be associated with a higher rate of complications including stent thrombus and restenosis.
Assuntos
Intervenção Coronária Percutânea/métodos , Trombocitemia Essencial/cirurgia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The A-kinase anchoring proteins (AKAPs) are a group of structurally diverse proteins identified in various species and tissues. These proteins are able to anchor protein kinase and other signalling proteins to regulate cardiac function. Acting as a scaffold protein, AKAPs ensure specificity in signal transduction by enzymes close to their appropriate effectors and substrates. Over the decades, more than 70 different AKAPs have been discovered. Accumulative evidence indicates that AKAPs play crucial roles in the functional regulation of cardiac diseases, including cardiac hypertrophy, myofibre contractility dysfunction and arrhythmias. By anchoring different partner proteins (PKA, PKC, PKD and LTCCs), AKAPs take part in different regulatory pathways to function as regulators in the heart, and a damaged structure can influence the activities of these complexes. In this review, we highlight recent advances in AKAP-associated protein complexes, focusing on local signalling events that are perturbed in cardiac diseases and their roles in interacting with ion channels and their regulatory molecules. These new findings suggest that AKAPs might have potential therapeutic value in patients with cardiac diseases, particularly malignant rhythm.
Assuntos
Proteínas de Ancoragem à Quinase A/metabolismo , Cardiopatias/fisiopatologia , Animais , Cardiopatias/metabolismo , Humanos , Transdução de SinaisRESUMO
BACKGROUND: Numerous studies have demonstrated that fibroblast growth factor-2 (FGF-2) signaling may play a pivotal role in the development of pulmonary arterial hypertension (PAH). Excessive endothelial FGF-2 contributes to smooth muscle hyperplasia and disease progression. PD173074 is a potent FGF receptor 1 (FGFR-1) inhibitor that displays high activity and selectivity. The aim of this study was to investigate the effects of PD173074 on monocrotaline-induced PAH. We also evaluated whether FGFR-1 inhibition could attenuate bone morphogenetic protein type II receptor (BMPR-II) downregulation in the monocrotaline model. METHODS: PAH model was established by a single intraperitoneal injection of monocrotaline. And then a daily intraperitoneal injection of PD173074 (20 mg/kg) was administered from day 14 to day 28. Hemodynamic parameters, right ventricular hypertrophy index and morphometry were evaluated at day 28. Western blot and immunohistochemical analyses were used to determine the expression of FGF-2 and bone morphogenetic protein signaling in the lung tissue. RESULTS: The expression of FGF-2 and FGFR-1 was upregulated in lung tissue after monocrotaline injection and it was accompanied by hemodynamic changes and pulmonary vascular remodeling. PD173074 treatment ameliorated PAH and vascular remodeling. It decreased ERK1/2 activation and rescued total Akt expression, leading to a reduction in both proliferation and apoptosis in the lung. Besides, PD173074 rescued the expression of BMPR-II and p-Smad 1/5/8. CONCLUSION: These results suggest that PD173074 can alleviate monocrotaline-induced pulmonary arterial hypertension and it may be a useful option for PAH. Our data also suggest a role of FGF-2/bone morphogenetic protein signaling interaction in PAH.
Assuntos
Arteríolas/efeitos dos fármacos , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Hipertensão Pulmonar/tratamento farmacológico , Pulmão/irrigação sanguínea , Monocrotalina , Pirimidinas/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Adolescente , Adulto , Animais , Apoptose/efeitos dos fármacos , Arteríolas/metabolismo , Arteríolas/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Masculino , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad Reguladas por Receptor/metabolismo , Fatores de Tempo , Remodelação Vascular/efeitos dos fármacos , Adulto JovemRESUMO
BACKGROUND: Previous studies have demonstrated that platelet activation occurs in patients with pulmonary arterial hypertension (PAH). Mean platelet volume (MPV) and platelet distribution width (PDW) are two markers of platelet activation, and have recently been recognised as risk predictors of cardiovascular diseases. This study aimed to investigate whether MPV and PDW would be useful to reflect disease severity and predict prognosis in idiopathic PAH (IPAH). METHODS: MPV and PDW levels were measured in 82 IPAH patients without antiplatelet or anticoagulant treatment on admission and 82 healthy controls. Concurrent collected data included clinical, haemodynamic and biochemical variables. All patients were followed-up from the date of blood testing. The endpoint was all-cause mortality. RESULTS: MPV and PDW were significantly higher in patients with IPAH than in age and sex-matched control subjects (11.4±0.9fl vs. 10.3±0.9fL and 14.3±2.9% vs. 11.9±1.9%, respectively; p=0.000). Pearson's correlation analysis revealed that MPV and PDW correlated positively with right ventricular systolic pressure, mean pulmonary arterial pressure and pulmonary vascular resistance. After a mean follow-up of 14±8 months, 12 patients died of right heart failure. Receiver operating characteristic analysis showed that MPV and PDW could not predict all-cause mortality. Multivariate Cox regression analysis suggested that right/left ventricular end-diastolic diameter ratio and NT-proBNP were independent predictive parameters of all-cause mortality. CONCLUSIONS: Our results suggest that MPV and PDW were elevated in patients with IPAH. They could partly reflect disease severity, but did not predict prognosis.
Assuntos
Hipertensão Pulmonar Primária Familiar/sangue , Hipertensão Pulmonar Primária Familiar/fisiopatologia , Volume Plaquetário Médio , Ativação Plaquetária , Adulto , Análise de Variância , Biomarcadores/sangue , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/fisiopatologia , Masculino , Análise Multivariada , Contagem de Plaquetas , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: Oral targeted therapies have been widely used in the treatment of pulmonary arterial hypertension (PAH). Many new oral agents emerge for PAH in recent years. In this study, we performed a meta-analysis to evaluate the efficacy and safety of oral targeted therapies in PAH, focusing on overall survival improvement. METHODS: Randomized controlled trials of oral targeted therapies in patients with PAH published through September 2013 were identified by searching the Cochrane Library, EMBASE, and PUBMED databases. We calculated risk ratios for dichotomous data and weighted mean differences with 95% confidence intervals for continuous data. RESULTS: 18 trials with a total of 4363 subjects were indentified in the meta-analysis. Analysis by drug class revealed that phosphodiesterase type 5 inhibitors (PDE-5Is) were associated with a statically significant reduction in mortality (RR 0.22; 95% CI 0.07-0.71, p = 0.011), while other drugs only showed a trend toward reducing mortality. Compared with placebo, endothelin receptor antagonists (ERAs), PDE-5Is and riociguat significantly reduced clinical worsening, ameliorated WHO function class, and increased the 6-min walk distance. However, oral prostanoids only showed a mild effect on 6-min walk distance (19.88 m; 95% CI 10.12-29.64, p = 0.000), and did not have any effect on reducing mortality and clinical worsening. Moreover, oral prostanoids significantly increased the incidence of withdrawal due to adverse effects (RR 3.41; 95% CI 2.06-5.63, p = 0.000). CONCLUSIONS: This meta-analysis suggests that all oral agents confer a therapeutic benefit. Of these, only PDE-5Is has a proven survival benefit. ERAs and riociguat are efficient in reducing clinical worsening, and ameliorating exercise capacity. Oral prostanoids have the significant adverse effects and weak therapeutic effects.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Administração Oral , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Antagonistas dos Receptores de Endotelina/administração & dosagem , Antagonistas dos Receptores de Endotelina/efeitos adversos , Antagonistas dos Receptores de Endotelina/uso terapêutico , Humanos , Hipertensão Pulmonar/mortalidade , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/efeitos adversos , Inibidores da Fosfodiesterase 5/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Prostanoids have played an important role in the treatment of pulmonary arterial hypertension (PAH). However, whether prostanoid therapy provides a survival advantage is still not clear. The aim of this meta-analysis was to evaluate the efficacy and safety of prostanoids in PAH, focusing on the improvement in overall survival. METHODS: Trials were identified from the Cochrane Library, EMBASE, and PUBMED databases. We calculated risk ratios (RR) for dichotomous data and weighted mean differences with 95 % confidence intervals (CI) for continuous data. RESULTS: Fourteen trials with a total of 2,244 adult patients (1,189 patients in the prostanoid treatment group and 1,055 patients in the placebo group) were included in the meta-analysis. All-cause mortality rate in the control group was 4.17 %. In a 13.4-week follow-up, prostanoid treatment was associated with a 44 % reduction in mortality (RR 0.56; 95 % CI 0.35-0.88; P = 0.01).Subgroup analysis suggested that only treatment with intravenous prostanoids provided a survival benefit. Compared with placebo, prostanoids significantly reduced clinical worsening (RR 0.60; 95 % CI 0.46-0.80; P = 0.0003), increased the 6-min walk distance by 27.95 m, reduced mean pulmonary arterial pressure and pulmonary vascular resistance, and increased the cardiac index and mixed venous oxygen saturation. However, patients receiving prostanoid treatment showed a much higher incidence (RR 3.25; 95 % CI 2.07-5.10; P<0.00001) of withdrawal due to its adverse effects. CONCLUSION: The results of this meta-analysis suggest that treatment with prostanoids improves the survival of patients with PAH.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Prostaglandinas/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Hipertensão Pulmonar Primária Familiar , Hemodinâmica , Humanos , Hipertensão Pulmonar/mortalidade , Hipertensão Pulmonar/fisiopatologia , Prostaglandinas/efeitos adversos , CaminhadaRESUMO
OBJECTIVE: An obesity paradox, a "paradoxical" decrease in morbidity and mortality with increasing body mass index (BMI), has been shown in patients with heart failure. However, the impact of BMI in patients with idiopathic pulmonary arterial hypertension (IPAH) has not been studied. This study aims to find out whether BMI is a prognostic factor in IPAH. METHODS AND RESULTS: We analysed 173 patients with IPAH. The patients were subclassified into categories of BMI defined as: under-weight (< 18.5 kg/m2), normal weight (18.5 to 24.9 kg/m2), overweight and obese (25 to 34.9 kg/m2). The three BMI groups had similar profiles in terms of haemodynamic parameters assessed by right heart catheterization and level of NT-proBNP. The overweight and obese group had higher age, and lower WHO functional class, larger left ventricular end-diastolic dimensions (LVEDDs) than the other two groups.The Kaplan-Meier survival curves for the three BMI categories demonstrated that the overweight and obese group had a significantly higher survival rate than the normal weight and underweight groups (log-rank test, P = 0.027, P = 0.000, respectively). In a stepwise forward regression, lower BMI, higher WHO functional class, lower cardiac index, smaller LVEDDs and absence of targeted medication remained independent predictors of mortality. CONCLUSIONS: Excess body mass is a protective factor for death in patients with IPAH.
Assuntos
Índice de Massa Corporal , Hipertensão Pulmonar Primária Familiar/mortalidade , Obesidade/epidemiologia , Adulto , Biomarcadores/sangue , Cateterismo Cardíaco , Feminino , Humanos , Masculino , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Prognóstico , Fatores de Risco , Taxa de SobrevidaRESUMO
Objects: This study aimed to explore the association between the Systemic Immune-Inflammation Index (SII) and diabetes mellitus (DM) and to assess its influence on the prognosis of the DM and no-DM groups. Methods: The study used data from the National Health and Nutrition Examination Survey; 9643 participants were included. Logistic regression analysis was employed to evaluate connections between SII and DM. We used the Cox proportional hazards model, restricted cubic spline, and Kaplan-Meier curve to analyze the relationship between SII and mortality. Results: The logistic regression analysis indicated that a significant increase in the likelihood of developing DM with higher SII levels (odds ratio, 1.31; 95% CI, 1.09-1.57, P = .003). The Cox model showed that there is a positive association between increased SII and higher all-cause mortality. The hazard ratios for SII were 1.53 (1.31, 1.78), 1.61 (1.31, 1.98), and 1.41 (1.12, 1.78) in the total, DM and non-DM groups, respectively. We observed a linear correlation between SII and all-cause mortality in DM participants, whereas non-DM participants and the total population showed a nonlinear correlation. Conclusion: Elevated SII levels are linked to an augmented risk of DM. Those with DM and higher SII levels demonstrated an elevated risk of mortality.
RESUMO
Filamin A (FLNA) is a high molecular weight cytoskeleton protein important for cell locomotion. A relationship between FLNA mutations and pulmonary arterial hypertension (PAH) has previously been reported; however, the detailed mechanism remains unclear. The present study aimed to explore the role of FLNA in vascular smooth muscle cells during the development of PAH. Smooth muscle cell (SMC)specific FLNAdeficient mice were generated and the mice were then exposed to hypoxia for 28 days to build the mouse model of PAH. Human pulmonary arterial smooth muscle cells (PASMCs) were also cultured and transfected with FLNA small interfering RNA or overexpression plasmids to investigate the effects of FLNA on PASMC proliferation and migration. Notably, compared with control individuals, the expression levels of FLNA were increased in lung tissues from patients with PAH, and it was obviously expressed in the PASMCs of pulmonary arterioles. FLNA deficiency in SMCs attenuated hypoxiainduced pulmonary hypertension and pulmonary vascular remodeling. In vitro studies suggested that absence of FLNA impaired PASMC proliferation and migration, and produced lower levels of phosphorylated (p)PAK1 and RAC1 activity. However, FLNA overexpression promoted PASMC proliferation and migration, and increased the expression levels of pPAK1 and RAC1 activity. The present study highlights the role of FLNA in pulmonary vascular remodeling; therefore, it could serve as a potential target for the treatment of PAH.
Assuntos
Filaminas , Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Animais , Humanos , Camundongos , Proliferação de Células , Células Cultivadas , Filaminas/genética , Filaminas/metabolismo , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Hipóxia/complicações , Hipóxia/genética , Hipóxia/metabolismo , Miócitos de Músculo Liso/metabolismo , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/metabolismo , Artéria Pulmonar/metabolismo , Transdução de Sinais , Remodelação Vascular/genéticaRESUMO
BACKGROUND: Astrocytes and metabotropic glutamate receptors play important roles in nociceptive processing. However, their roles in bone cancer pain were not well understood. This study sought to investigate whether selective mGluR3 and mGluR5 agonist or antagonist develop antinociceptive effects on bone cancer pain by inhibition of spinal astrocyte activation. METHODS: C3H/HeNCrlVr mice were inoculated into the intramedullary space of the femur with sarcoma NCTC 2472 cells to induce bone cancer pain. Quantitative real-time reverse transcription-polymerase chain reaction and Western blot experiments examined messenger RNA and protein expression of spinal glial fibrillary acidic protein, mGluR3, and mGluR5. The authors further investigated effects of intrathecal treatment with the mGluR3 agonist (APDC), the mGluR3 antagonist (LY341495), the mGluR5 agonist (CHPG), or the mGluR5 antagonist (MTEP) on nociceptive behaviors and spinal astrocyte activation associated with bone cancer pain. RESULTS: Inoculation of sarcoma cells, but not α-MEM solution, induced progressive bone cancer pain and resulted in up-regulation of glial fibrillary acidic protein, mGluR3, and mGluR5 expression on days 10, 14, and 21 postinoculation. Intrathecal administration of APDC and MTEP attenuated bone cancer-evoked spontaneous pain, mechanical allodynia, thermal hyperalgesia, and reduced spinal glial fibrillary acidic protein expression. However, treatment with LY341495 and CHPG induced thermal hyperalgesia and spinal glial fibrillary acidic protein expression in control mice. CONCLUSIONS: Spinal mGluR3 activation or mGluR5 inhibition reduced bone cancer pain. Inhibition of spinal astrocyte activation may contribute to the analgesic effects. These findings may lead to novel strategies for the treatment of bone cancer pain.
Assuntos
Astrócitos/efeitos dos fármacos , Neoplasias Ósseas/complicações , Osteossarcoma/complicações , Dor Intratável/tratamento farmacológico , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Medula Espinal/citologia , Animais , Comportamento Animal/efeitos dos fármacos , Western Blotting , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proteína Glial Fibrilar Ácida/biossíntese , Membro Posterior/fisiologia , Temperatura Alta , Hiperalgesia/tratamento farmacológico , Injeções Espinhais , Masculino , Camundongos , Camundongos Endogâmicos C3H , Transplante de Neoplasias , Osteossarcoma/patologia , Medição da Dor/efeitos dos fármacos , Dor Intratável/etiologia , Estimulação Física , Reação em Cadeia da Polimerase em Tempo Real , Receptor de Glutamato Metabotrópico 5 , Medula Espinal/efeitos dos fármacosRESUMO
Right ventricular (RV) failure determines the prognosis in pulmonary arterial hypertension (PAH), but the underlying mechanism is still unclear. Growing evidence has shown that microRNAs participate in RV remodeling. This study is undertaken to explore the role of miR-335-5p in regulating RV remodeling induced by PAH. Two PAH models were used in the study, including the monocrotaline rat model and hypoxia/su5416 mouse model. miRNA sequencing and RT-qPCR validation identified that miR-335-5p was elevated in the RV of PAH rats. In vitro, miR-335-5p expression was increased after angiotensin II treatment, and miR-335-5p inhibition relieved angiotensin II-induced cardiomyocyte hypertrophy. The luciferase reporter assay showed that calumenin was a target gene for miR-335-5p. Pretreatment with miR-335-5p inhibitors could rescue calumenin downregulation induced by angiotensin II in H9C2 cells. Moreover, intracellular Ca2+ concentration and apoptosis were increased after angiotensin II treatment, and miR-335-5p inhibition decreased intracellular Ca2+ accumulation and apoptosis. Finally, in vivo miR-335-5p downregulation (antagomir miR-335-5p) attenuated RV remodeling and rescued calumenin downregulation under conditions of hypoxia/su5416 exposure. Our work highlights the role of miR-335-5p and calumenin in RV remodeling and may lead to the development of novel therapeutic strategies for right heart failure.
Assuntos
Hipertensão Pulmonar , MicroRNAs , Hipertensão Arterial Pulmonar , Angiotensina II/metabolismo , Animais , Antagomirs , Hipertensão Pulmonar Primária Familiar , Hipertensão Pulmonar/metabolismo , Hipóxia/genética , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Monocrotalina , Hipertensão Arterial Pulmonar/genética , Ratos , Regulação para Cima/genética , Remodelação Ventricular/genéticaRESUMO
BACKGROUND: Tumor necrosis factor α (TNF-α) may have a pivotal role in the genesis of mechanical allodynia and thermal hyperalgesia during inflammatory and neuropathic pain. Thalidomide has been shown to selectively inhibit TNF-α production. Previous studies have suggested that thalidomide exerts anti-nociceptive effects in various pain models, but its effects on bone cancer pain have not previously been studied. Therefore, in the present study, we investigated the effect of thalidomide on bone cancer-induced hyperalgesia and up-regulated expression of spinal TNF-α in a mouse model. RESULTS: Osteosarcoma NCTC 2472 cells were implanted into the intramedullary space of the right femurs of C3H/HeJ mice to induce ongoing bone cancer related pain behaviors. At day 5, 7, 10 and 14 after operation, the expression of TNF-α in the spinal cord was higher in tumor-bearing mice compared to the sham mice. Intraperitoneal injection of thalidomide (50 mg/kg), started at day 1 after surgery and once daily thereafter until day 7, attenuated bone cancer-evoked mechanical allodynia and thermal hyperalgesia as well as the up-regulation of TNF-α in the spinal cord. CONCLUSIONS: These results suggest that thalidomide can efficiently alleviate bone cancer pain and it may be a useful alternative or adjunct therapy for bone cancer pain. Our data also suggest a role of spinal TNF-α in the development of bone cancer pain.
Assuntos
Neoplasias Ósseas/complicações , Dor/tratamento farmacológico , Dor/etiologia , Medula Espinal/metabolismo , Talidomida/administração & dosagem , Talidomida/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Linhagem Celular Tumoral , Modelos Animais de Doenças , Injeções Intraperitoneais , Masculino , Camundongos , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Talidomida/farmacologia , Fatores de TempoRESUMO
Oral targeted therapies play an important role in the treatment of pulmonary arterial hypertension (PAH). Several new oral agents have emerged for PAH in recent years. However, whether they provide a survival advantage is still not clear. This meta-analysis aimed to assess the efficacy and safety of oral targeted therapies, especially on predefined clinical worsening events. Trials were searched in the Cochrane Library, EMBASE, and PUBMED databases through June 2018. We calculated risk ratios for dichotomous data and weighted mean differences with 95% confidence intervals (CI) for continuous data. Twenty-five trials with a total of 6847 participants were included in the meta-analysis. Oral targeted therapies were associated with significant risk reduction in clinical worsening compared with placebo (relative risk [RR] 0.64; 95% CI = 0.58-0.70; P < 0.001). This reduction in risk was driven by reduction in non-fatal endpoints, including PAH-related admissions to hospital (RR = 0.66; 95% CI = 0.56-0.76; P < 0.001), treatment escalation (RR = 0.43; 95% CI = 0.28-0.66; P < 0.001), and symptomatic progression (RR = 0.55; 95% CI = 0.48-0.64; P < 0.001), but not by reduction of mortality (RR = 0.87; 95% CI = 0.68-1.12; P = 0.215). Oral targeted therapies were also associated with improvement in 6-min walk distance (26.62 m; 95% CI = 20.54-32.71; P < 0.001) and World Health Organization functional class (RR = 1.36; 95% CI = 1.20-1.54; P < 0.001). The results of this meta-analysis showed the benefits of oral treatments on clinical worsening events in PAH. However, these oral agents did not show any survival benefit in the short-term follow-up.
RESUMO
BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction, vascular remodelling, and microthrombotic events. Inflammatory cytokine interleukin (IL-6) may be a key factor in the development of PAH, and glycoprotein 130 (Gp130) is an important signal-transducing subunit of IL-6. The aim of our study was to evaluate the effectiveness of Gp130 inhibitor in reducing inflammation and ameliorating PAH-related vascular remodelling in monocrotaline (MCT)-exposed rats. METHODS: Sprague-Dawley rats (n = 96; weight, 240-250 g) were randomly divided into 3 groups: control, MCT-exposed (MCT), and MCT-exposed plus Gp130 inhibitor (MCT-Gp) administered daily (5 mg/kg) from days 14-28. Eight rats were killed in each group at weeks 1 through 4, with the following measured variables compared across groups on day 28: hemodynamics, right ventricular hypertrophy, morphometric measurements, immunohistochemical results, levels of IL-6, phosphorylated signal transducer and activator of transcription 3, proliferating cell nuclear antigen (PCNA), bone morphogenetic protein receptor-2 (BMPR2), proangiogenic factor, vascular endothelial growth factor (VEGF), proproliferative kinase extracellular signal-regulated kinase (ERK), survivin, Bcl-2, and Bax. RESULTS: Compared with the MCT group, Gp130 inhibitor, after MCT exposure, improved hemodynamics and significantly reduced the severity of inflammation, as estimated by levels of IL-6 (P < 0.0001), and reversed pulmonary arterial remodelling, as assessed by medial wall thickness (P < 0.0001). Gp130 inhibitor upregulated BMPR2 expression in MCT-exposed lungs (P = 0.040) and decreased the expression of PCNA, VEGF, ERK, and survivin (all P < 0.05). CONCLUSIONS: Gp130 inhibitor upregulated BMPR2 expression in MCT-exposed lungs, restored the BMPR2/IL-6 balance, reduced IL-6-associated inflammation, inhibited pulmonary artery smooth muscle cell proliferation, and ameliorated pulmonary vascular remodelling in MCT-induced PH in rats.
Assuntos
Glicoproteínas/antagonistas & inibidores , Hipertensão Pulmonar/tratamento farmacológico , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Citocinas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Pulmão/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Monocrotalina/toxicidade , Antígeno Nuclear de Célula em Proliferação/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Ratos Sprague-Dawley , Survivina , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Spinal nitric oxide is involved in the mechanisms of pain generation and transmission during inflammatory and neuropathic pain. The aim of the present study was to explore the role of spinal nitric oxide in the development of bone cancer pain. 2 x 10(5) osteosarcoma cells were implanted into the intramedullary space of right femurs of C3H/HeJ mice to induce a model of ongoing bone cancer. Polymerase chain reaction and immunohistochemical analyses were performed to assess the expression of neuronal nitric oxide synthase (nNOS) and inducible (i)NOS in the spinal cord following inoculation. The results showed that inoculation of osteosarcoma cells induced progressive bone cancer, accompanied with pain-associated behavior. The levels of nNOS mRNA in the spinal cord of tumor mice began to increase at day 10 and then decreased to the level in sham mice at day 14, while iNOS mRNA markedly increased in the tumor group at days 10 and 14. Immunohistochemical analysis showed that nNOS- and iNOS-positive neurons were mainly located in the superficial dorsal horn and around the central canal of the L3-L5 spinal cord. Intrathecal injection of 50 µg NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) attenuated cancer-evoked pain behaviors at day 14. These findings indicated that an upregulation of nNOS and iNOS in the spinal cord is associated with bone cancer pain and suggests that exogenously administered L-NMMA may have beneficial effects to alleviate bone cancer pain.