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1.
Biochem Biophys Res Commun ; 511(1): 179-184, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30777331

RESUMO

Vascular remodeling, resulting from proliferation and migration of vascular smooth muscle cells (VSMCs), is a major cause of atherosclerosis and restenosis. The lysophospholipid mediator sphingosine-1-phosphate (S1P) regulates proliferation and migration of VSMCs via S1P-specific G protein-coupled receptors, including S1P receptor 1 (S1PR1) to S1PR3. However, the role of S1PR1 in vascular remodeling is not well understood. Therefore, in this study, we aimed to investigate the effect of S1PR1 on neointimal hyperplasia in a carotid artery ligation mouse model using transgenic C57Bl/6 mice that overexpressed S1PR1 (Tg-S1PR1) under the control of α-smooth muscle actin promoter. We found that S1PR1 expression in carotid artery was upregulated after carotid artery ligation in non-transgenic (nTg) mice. Tg-S1PR1 mice showed enhanced ligation-induced neointimal hyperplasia with increased neointimal cell proliferation, compared with control nTg mice. VSMCs isolated from Tg-S1PR1 mice showed enhanced proliferation and migration in response to S1P stimulation. VSMCs from Tg-S1PR1 mice showed greater expression of interleukin-6 (IL-6) compared with nTg mouse-derived VSMCs, and administration of IL-6-neutralizing antibody into Tg-S1PR1 mice suppressed neointimal hyperplasia. These results suggest that S1P-S1PR1 signaling plays an important role in neointimal hyperplasia after vascular injury via IL-6 production.


Assuntos
Artérias Carótidas/patologia , Lesões das Artérias Carótidas/patologia , Neointima/patologia , Receptores de Esfingosina-1-Fosfato/metabolismo , Animais , Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/genética , Lesões das Artérias Carótidas/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Hiperplasia/genética , Hiperplasia/metabolismo , Hiperplasia/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Neointima/genética , Neointima/metabolismo , Receptores de Esfingosina-1-Fosfato/análise , Receptores de Esfingosina-1-Fosfato/genética , Regulação para Cima
2.
J Med Case Rep ; 15(1): 11, 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33451341

RESUMO

BACKGROUND: Caffeine is a widely used dietary stimulant, and cases of caffeine overdoses, sometimes leading to death, are increasing. We encountered a case of caffeine intoxication resolved with administration of the sedative agent dexmedetomidine. CASE PRESENTATION: We administered dexmedetomidine for sedation and to suppress sympathetic nerve stimulation in the case of an 18-year-old Japanese male who ingested a massive dose of caffeine with the intention of committing suicide. The patient was in an excited state and had hypertension, sinus tachycardia, and hypokalemia with prominent QT prolongation. After dexmedetomidine administration, the patient's mental state, hemodynamics, and electrolyte levels were improved immediately. He was discharged without any sequelae 3 days later. CONCLUSION: Cases of acute caffeine intoxication with agitation, sympathetic overactivity and adverse cardiac events would benefit with dexmedetomidine treatment.


Assuntos
Cafeína/intoxicação , Estimulantes do Sistema Nervoso Central/intoxicação , Dexmedetomidina/uso terapêutico , Overdose de Drogas/tratamento farmacológico , Hipnóticos e Sedativos/uso terapêutico , Tentativa de Suicídio , Acidose Láctica/induzido quimicamente , Acidose Láctica/tratamento farmacológico , Adolescente , Antídotos/uso terapêutico , Carvão Vegetal/uso terapêutico , Eletrocardiografia , Lavagem Gástrica , Humanos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipopotassemia/induzido quimicamente , Hipopotassemia/tratamento farmacológico , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/tratamento farmacológico , Masculino , Potássio/uso terapêutico , Taquicardia/induzido quimicamente , Taquicardia/tratamento farmacológico
3.
J Cardiol ; 72(1): 81-86, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29317133

RESUMO

BACKGROUND: In patients with coronary artery disease (CAD), one of the risk models available in Japan was a multivariate risk prediction model based on a Japanese multicenter database: the Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated SPECT (J-ACCESS). The aim of this study was to clinically validate the accuracy of this risk model. METHODS: We evaluated the performance of the J-ACCESS model using data derived from the Assessment of the Predicted value of PROgnosis of cArdiaC events in Hokuriku (APPROACH) registry. Variables of age, summed stress score (SSS), left ventricular ejection fraction (LVEF), estimated glomerular filtration rate (eGFR), and diabetes mellitus were included. The major cardiac events were defined as cardiac death, non-fatal myocardial infarction, and heart failure that required hospitalization. The patients were followed up for three years to compare between predicted risk and actual events. RESULTS: We evaluated 283 patients with suspected or confirmed CAD receiving myocardial perfusion imaging using 99mTc-tetrofosmin between March 2009 and August 2011. Mean age was 68.9±10.1 years, mean eGFR 67.4±24.3mL/min/1.73m2, mean SSS 5.2±7.2, and mean LVEF 65.4±14.0%. Fourteen (4.9%) patients experienced major cardiac events including cardiac death in 4 patients (1.4%), non-fatal myocardial infarction in 1 patient (0.3%), and severe heart failure in 9 patients (3.2%), respectively. While SSS≥8, LVEF<50%, eGFR<45mL/min/1.73m2, and event risk≥10% were significant variables in survival analysis, multivariate proportional hazard analysis showed that only LVEF and eGFR were significant. The event rate estimated from the J-ACCESS model was comparable to the actual number of major cardiac events (9 and 6, respectively, p=0.58 by Chi-square test). CONCLUSIONS: The predictive ability of the J-ACCESS risk model is clinically valid among patients with CAD and could be applicable in clinical practice.


Assuntos
Doença da Artéria Coronariana/epidemiologia , Modelos Cardiovasculares , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Taxa de Filtração Glomerular , Insuficiência Cardíaca/epidemiologia , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Infarto do Miocárdio/epidemiologia , Imagem de Perfusão do Miocárdio , Prognóstico , Sistema de Registros , Volume Sistólico
4.
PLoS One ; 12(8): e0182329, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28771545

RESUMO

BACKGROUND: Cardiac fibroblasts, together with cardiomyocytes, occupy the majority of cells in the myocardium and are involved in myocardial remodeling. The lysophospholipid mediator sphigosine-1-phosphate (S1P) regulates functions of cardiovascular cells through multiple receptors including S1PR1-S1PR3. S1PR1 but not other S1P receptors was upregulated in angiotensin II-induced hypertrophic hearts. Therefore, we investigated a role of S1PR1 in fibroblasts for cardiac remodeling by employing transgenic mice that overexpressed S1PR1 under the control of α-smooth muscle actin promoter. In S1PR1-transgenic mouse heart, fibroblasts and/or myofibroblasts were hyperplastic, and those cells as well as vascular smooth muscle cells overexpressed S1PR1. Transgenic mice developed bi-ventricular hypertrophy by 12-week-old and diffuse interstitial fibrosis by 24-week-old without hemodynamic stress. Cardiac remodeling in transgenic mice was associated with greater ERK phosphorylation, upregulation of fetal genes, and systolic dysfunction. Transgenic mouse heart showed increased mRNA expression of angiotensin-converting enzyme and interleukin-6 (IL-6). Isolated fibroblasts from transgenic mice exhibited enhanced generation of angiotensin II, which in turn stimulated IL-6 release. Either an AT1 blocker or angiotensin-converting enzyme inhibitor prevented development of cardiac hypertrophy and fibrosis, systolic dysfunction and increased IL-6 expression in transgenic mice. Finally, administration of anti-IL-6 antibody abolished an increase in tyrosine phosphorylation of STAT3, a major signaling molecule downstream of IL-6, in the transgenic mouse heart and prevented development of cardiac hypertrophy in transgenic mice. These results demonstrate a promoting role of S1PR1 in cardiac fibroblasts for cardiac remodeling, in which angiotensin II-AT1 and IL-6 are involved.


Assuntos
Angiotensina II/metabolismo , Interleucina-6/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Transdução de Sinais , Angiotensina II/análise , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Compostos de Bifenilo , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/patologia , Cardiomegalia/prevenção & controle , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Ventrículos do Coração/diagnóstico por imagem , Humanos , Interleucina-6/análise , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Fosforilação/efeitos dos fármacos , Plasmídeos/genética , Plasmídeos/metabolismo , Receptores de Lisoesfingolipídeo/genética , Transdução de Sinais/efeitos dos fármacos , Tetrazóis/farmacologia , Tetrazóis/uso terapêutico
5.
Open Heart ; 3(1): e000400, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27403330

RESUMO

OBJECTIVE: Comprehensive profiling of gene expression in peripheral blood leucocytes (PBLs) in patients with acute coronary syndrome (ACS) as a prognosticator is needed. We explored the specific profile of gene expression in PBLs in ACS for long-term risk stratification. METHODS: 30 patients with ACS who underwent primary percutaneous coronary intervention (PCI) and 15 age-matched adults who participated in medical check-ups were enrolled from three centres. Peripheral blood samples were collected to extract RNA for microarray analyses. RESULTS: During the 5-year follow-up, 36% of this cohort developed the expected non-fatal coronary events (NFEs) of target lesion revascularisation (TLR) and PCI for a de novo lesion. Class comparison analysis (p<0.005) demonstrated that 83 genes among 7785 prefiltered genes (41 upregulated vs 42 downregulated genes) were extracted to classify the patients according to the occurrence of NFE. Pathway analysis based on gene ontology revealed that the NFEs were associated with altered gene expression regarding the T-cell receptor signalling pathway in ACS. Univariate t test showed that the expression level of death-associated protein kinase1 (DAPK1), known to regulate inflammation, was the most significantly negatively regulated gene in the event group (0.61-fold, p<0.0005). Kaplan-Meier curve analysis and multivariate analysis adjusted for baseline characteristics or clinical biomarkers demonstrated that lower DAPK1 expression in PBL emerged as an independent risk factor for the NFEs (HR: 8.73; CI 1.05 to 72.8, p=0.045). CONCLUSIONS: Altered gene expression in T-cell receptor signalling in PBL in ACS could be a prognosticator for secondary coronary events. TRIAL REGISTRATION NUMBER: UMIN000001932; Results.

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