RESUMO
Histone deacetylases (HDACs) are a vast family divided into four major classes: class I (1, 2, 3, and 8), class II (4, 5, 6, 7, 9 and 10), class III (sirtuin family) and class IV (HDAC11). HDAC inhibition attenuates cardiac hypertrophy through suppression of the mechanistic target of rapamycin complex1 (mTORC1) signaling. HDAC inhibitors upregulate the expression of tuberous sclerosis complex 2 (TSC2), an mTORC1 inhibitor. However, the molecular mechanism underlying HDAC inhibitor-mediated upregulation of TSC2 is unclear. We hypothesized that an HDAC inhibitor, CG200745 (CG), ameliorates cardiac hypertrophy through the inhibition of mTORC1 signaling by upregulating of the CCAAT/enhancer-binding protein-ß (C/EBP-ß)/TSC2 pathway. To establish a cardiac hypertrophy model, deoxycorticosterone acetate (DOCA, 40 mg/kg/wk) was subcutaneously injected for 4 weeks into Sprague-Dawley rats. All rats were unilaterally nephrectomized and had free access to drinking water containing 1% NaCl with or without CG of different concentrations. The expression level of TSC2 and C/EBP-ß was measured by quantitative real-time PCR (qRT-PCR) and western blot analysis. Acetylation of C/EBP-ß was analyzed by immunoprecipitation. The recruitment of C/EBP-ß and polymerase II (Pol II) on TSC2 promoter region was analyzed by chromatin immunoprecipitation (ChIP). CG treatment increased the expression of TSC2. In addition, CG treated rats showed an increased in the expression and acetylation of C/EBP-ß, owing to the increase in the recruitment of C/EBP-ß and Pol II at Tsc2 gene promoter. Thus, CG ameliorates cardiac hypertrophy through the inhibition of mTORC1 signaling via upregulation of the C/EBP-ß/TSC2 pathway in DOCA-induced hypertensive rats.
Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Coração/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Miocárdio/patologia , Naftalenos/farmacologia , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Regulação para Cima/efeitos dos fármacos , Acetilação/efeitos dos fármacos , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Cardiotônicos/farmacologia , Acetato de Desoxicorticosterona/efeitos adversos , Hipertrofia/induzido quimicamente , Hipertrofia/metabolismo , Hipertrofia/patologia , Hipertrofia/prevenção & controle , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Miocárdio/metabolismo , Regiões Promotoras Genéticas/genética , Ratos , Ratos Sprague-Dawley , Proteína 2 do Complexo Esclerose Tuberosa/genética , Remodelação Ventricular/efeitos dos fármacosRESUMO
BACKGROUND: A test panel is a group of tests that are simultaneously performed for diagnosis and follow-up of patients. Organ-specific or disease-specific test panels are currently available. Since the patient's chief complaint plays a key role in obtaining the personal and medical history and performing physical examinations, we proposed a test panel based on the chief complaints of the patients. METHODS: We collected data from 3,127 adults with apparent symptoms who visited the emergency department from April 2009 to May 2009. Subsequently, we classified the patients' chief complaints, ordered the laboratory tests on the basis of these complaints, considered the patients' disease entities, and reviewed the relevant literature. RESULTS: The patients were categorized into 14 groups on the basis of the most common chief complaints presented in the emergency department. We first selected the basic test panels and then organized the test panel for each chief complaint to enable differential diagnosis. CONCLUSIONS: We proposed test panels based on the chief complaints of the patients; these test panels could allow rapid diagnosis and be more useful than the organ-specific or disease-specific tests in critical pathway development. The next step will be evaluating the efficiency and cost effectiveness of the test panel that we suggested.
