RESUMO
BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a progressive subtype of non-alcoholic fatty liver disease (NAFLD) that is closely related to cardiovascular disease (CVD). Nitric oxide (NO) plays a critical role in the control of various biological processes. Dysfunction of the NO signaling pathway is associated with various diseases such as atherosclerosis, vascular inflammatory disease, and diabetes. Recently, it has been reported that NO is related to lipid and cholesterol metabolism. Chronic NO synthase (NOS) inhibition accelerates NAFLD by increasing hepatic lipid deposition. However, the detailed relationship between NO and abnormal lipid and cholesterol metabolism in NAFLD/NASH has not been completely explained. We aimed to determine the effects of NOS inhibition by N omega-nitro-L-arginine methyl ester hydrochloride (L-NAME), a NOS inhibitor, on NASH and CVD via lipid and cholesterol metabolism. METHODS: Stroke-prone spontaneously hypertensive rats were fed a high-fat and high-cholesterol diet for 8 weeks and administered L-NAME for the last 2 weeks. Following blood and tissue sampling, biochemical analysis, histopathological staining, quantitative RT-PCR analysis, and western blotting were performed. RESULTS: L-NAME markedly increased hepatic triglyceride (TG) and cholesterol levels by promoting TG synthesis and cholesterol absorption from the diet. L-NAME increased the mRNA levels of inflammatory markers and fibrotic areas in the liver. Cholesterol secretion from the liver was promoted in rats administered L-NAME, which increased serum cholesterol. L-NAME significantly increased the level of oxidative stress marker and lipid deposition in the arteries. CONCLUSIONS: NOS inhibition simultaneously aggravates NASH and atherosclerosis via hepatic lipid and cholesterol metabolism.
Assuntos
Aterosclerose , Doenças Cardiovasculares , Hepatopatia Gordurosa não Alcoólica , Aceleração , Animais , Aterosclerose/metabolismo , Biomarcadores , Doenças Cardiovasculares/complicações , Colesterol , Dieta Hiperlipídica , Metabolismo dos Lipídeos , Fígado , NG-Nitroarginina Metil Éster/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Ratos , Ratos Endogâmicos SHRRESUMO
A high-fat/high-cholesterol (HFC) diet, but not a high-cholesterol (HC) diet, is known to induce elevated serum apolipoprotein E (apoE)-rich high-density lipoprotein (HDL) levels in animal models. However, the exact mechanisms by which the combination of dietary fat and cholesterol induces apoE-rich HDL production is not well understood. Here, we investigated the effects of dietary fat and cholesterol on serum lipoprotein profiles and hepatic mRNA expression that are associated with HDL production, cholesterol transport, and bile acid metabolism. Male Sprague-Dawley rats were fed HFC, HC, high-fat, or control diets and then evaluated. The HFC diet induced significant increases in hepatic free-cholesterol accumulation (1.4-fold, p < 0.01) and serum apoE-rich HDL cholesterol (8.7-fold, p < 0.001) levels compared with the HC diet. The apoE-rich HDL induced by the HFC diet was remarkably rich in free cholesterol. Liver gene-expression was mostly similar between the HC and HFC diet groups. However, there was a significant increase of ATP-binding cassette transporter A1 (ABCA1) levels in the HFC group compared to the HC group for both mRNA (1.9-fold, p < 0.001) and protein (6.6-fold, p < 0.01). These results suggest that an increase in apoE-rich HDL induced by dietary fat and cholesterol may be involved in cholesterol efflux from the liver through increased ABCA1-mediated free-cholesterol efflux.
Assuntos
Transportador 1 de Cassete de Ligação de ATP , Colesterol , Dieta Hiperlipídica , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Colesterol/efeitos adversos , Colesterol/metabolismo , HDL-Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/metabolismo , Fígado/metabolismo , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: High-density lipoprotein (HDL) containing apolipoprotein E (apoE-rich HDL) represents a small portion of plasma HDL. We recently established a method for measuring plasma apoE-rich HDL. This study aimed to investigate the relationship between metabolic syndrome (MetS) and apoE-rich HDL levels. METHODS: The apoE-rich HDL-cholesterol (HDL-C) levels and metabolic characteristics of 113 patients were analyzed. RESULTS: The MetS group (n = 58) had significantly lower apoE-rich HDL-C and a lower apoE-rich HDL-C/HDL-C ratio (apoE-HDL (%)) compared to the non-MetS group. The prevalence of MetS was increased when apoE-HDL (%) decreased. In simple regression analyses, apoE-HDL (%) was significantly inversely correlated with visceral fat area (rs = -0.370, P < 0.001) and plasma triglycerides (rs = -0.447, P < 0.001) and positively correlated with low-density lipoprotein (LDL) mean particle size (rs = 0.599, P < 0.001) and HDL mean particle size (rs = 0.512, P < 0.001). Stepwise multiple regression analysis revealed that LDL mean particle size, a component of the atherogenic lipoprotein profile, was an independent predictor of apoE-HDL (%) (adjusted R2 = 0.409). CONCLUSIONS: Plasma apoE-rich HDL levels might be a valuable indicator of MetS. These findings may help further understand HDL subfraction analysis in cardiometabolic diseases.
Assuntos
Síndrome Metabólica , Apolipoproteínas E , HDL-Colesterol , LDL-Colesterol , Humanos , Lipoproteínas HDL , TriglicerídeosRESUMO
AIM: Non-alcoholic steatohepatitis (NASH) increases cardiovascular risk regardless of risk factors in metabolic syndrome. However, the intermediary factors between NASH and vascular disease are still unknown because a suitable animal model has never been established. The stroke-prone (SP) spontaneously hypertensive rat, SHRSP5/Dmcr, simultaneously develops hypertension, acute arterial lipid deposits in mesenteric arteries, and NASH when feed with a high-fat and high-cholesterol (HFC) diet. We investigated whether SHRSP5/Dmcr affected with NASH aggravates the cardiac or vascular dysfunction. METHOD: Wister Kyoto and SHRSP5/Dmcr rats were divided into 4 groups of 5 rats each, and fed with a SP or HFC diet. After 8 weeks of HFC or SP diet feeding, glucose and insulin resistance, echocardiography, blood biochemistry, histopathological staining, and endothelial function in aorta were evaluated. RESULTS: We demonstrate that SHRSP5/Dmcr rats fed with a HFC diet presented with cardiac and vascular dysfunction caused by cardiac fibrosis, endothelial dysfunction, and left ventricular diastolic dysfunction, in association with NASH and hypertension. These cardiac and vascular dysfunctions were aggravated and not associated with the presence of hypertension, glucose metabolism disorder, and/or obesity. CONCLUSIONS: SHRSP5/Dmcr rats may be a suitable animal model for elucidating the organ interaction between NASH and cardiac or vascular dysfunction.
Assuntos
Colesterol na Dieta/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Endotélio Vascular/patologia , Fibrose/etiologia , Infarto do Miocárdio/etiologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Disfunção Ventricular Esquerda/etiologia , Animais , Diástole , Fibrose/patologia , Masculino , Infarto do Miocárdio/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Ratos , Ratos Endogâmicos SHR , Disfunção Ventricular Esquerda/patologiaRESUMO
Lavender essential oil (Lvn) has anti-inflammatory effects in an ovalbumin-sensitized murine model of asthma, and inhibits inflammatory cell infiltration into the lungs. The anti-inflammatory effects of Lvn on cell adhesion molecules are not clear. Here we evaluated the effects of Lvn and its main constituents, linalyl acetate (LA) and linalool (LO), on the expression of tumor necrosis factor-alpha (TNF-α)-induced cell adhesion molecules in murine brain endothelial bEnd.3 cells and human umbilical vein endothelial cells (HUVECs). The bEnd.3 cells were treated with Lvn, LA, or LO and subsequently stimulated with TNF-α. The mRNA expression levels of cell adhesion molecules were detected using RT-PCR. E-selectin and P-selectin protein and phosphorylated-NF-κB p65 were detected by western blotting. The effects of Lvn on HUVECs were measured by RT-PCR. In bEnd.3 cells, Lvn and LA suppressed TNF-α-induced E-selectin, P-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and phosphorylated-NF-κB p65 in the nucleus; LO did not suppress P-selectin or phosphorylated-NF-κB p65. Lvn inhibited TNF-α-induced E-selectin mRNA in HUVECs. These results indicate that Lvn and LA inhibit TNF-α-induced cell adhesion molecules in endothelial cells through the suppression of NF-κB activation. Consequently, Lvn or other essential oils including LA may be useful as alternative anti-inflammatory medicines.
Assuntos
Moléculas de Adesão Celular/análise , Células Endoteliais/efeitos dos fármacos , Monoterpenos/farmacologia , Óleos Voláteis/farmacologia , Óleos de Plantas/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Monoterpenos Acíclicos , Animais , Moléculas de Adesão Celular/genética , Células Endoteliais/química , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lavandula , Camundongos , NF-kappa B/fisiologia , Óleos Voláteis/análise , Óleos de Plantas/análise , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
BACKGROUND: High-density lipoprotein (HDL) containing apolipoprotein E (apoE-rich HDL) represents only a small portion of plasma HDL. Reliable methods for determining and isolating apoE-rich HDL have not been well studied. METHODS: We established a novel analytical method for apoE-rich HDL using polyethylene glycol and a cation-exchange column (PEG-column method). Furthermore, we examined biochemical correlates of apoE-rich HDL-cholesterol (HDL-C) in 36 patients who underwent coronary computed tomographic angiography. RESULTS: Our PEG-column method demonstrated high reproducibility (coefficient of variation <3.52%) and linearity up to 15mg/dl for apoE-rich HDL-C concentrations. Isolated apoE-rich HDL exhibited a larger diameter (14.8nm) than apoE-poor HDL (10.8nm) and contained both apoE and apoA-I. ApoE-rich HDL-C concentrations correlated significantly with triglycerides (rs=-0.646), LDL size (rs=0.472), adiponectin (rs=0.476), and other lipoprotein components. No significant correlation was obtained with the coronary calcium score. Multiple regression analysis revealed that plasma triglycerides and adiponectin concentrations remained significant independent predictors of apoE-rich (adjusted R2=0.486) but not apoE-poor HDL-C. CONCLUSIONS: The PEG-column method demonstrated, to various degrees, significant correlations between HDL subfractions and several lipid-related biomarkers involved in an atherogenic lipoprotein profile. Our separation technique for apoE-rich HDL is useful to clarify the role of apoE-rich HDL in atherosclerosis.
Assuntos
Apolipoproteínas E/sangue , Biomarcadores/sangue , Cromatografia por Troca Iônica/métodos , Lipoproteínas HDL/sangue , Adiponectina/sangue , Soluções Tampão , Cátions , Precipitação Química , Cromatografia por Troca Iônica/instrumentação , Angiografia por Tomografia Computadorizada , Feminino , Humanos , Magnésio/química , Masculino , Tamanho da Partícula , Projetos Piloto , Polietilenoglicóis/química , Reprodutibilidade dos Testes , Triglicerídeos/sangue , Adulto JovemRESUMO
AIMS: Lavender essential oil (Lvn) has been reported to have anti-inflammatory effects. Bronchial asthma is characterized by bronchial allergic inflammation with airway remodeling. Therefore, we evaluated the anti-inflammatory effect of Lvn on experimentally induced bronchial asthma in a murine model. MAIN METHODS: BALB/c mice were sensitized by an intraperitoneal injection of ovalbumin (OVA) at days 0 and 14, and subsequently challenged with nebulized OVA on days 28-30 (Control-Asthma group). Mice in the treatment group inhaled Lvn on days 14-31 (Lvn-Asthma group). The allergic inflammatory response was determined on days 32 and 33. KEY FINDINGS: An increase in airway resistance was inhibited in the Lvn-Asthma group than in the Control-Asthma group. The Lvn-Asthma group showed lower total cell numbers and eosinophils in bronchoalveolar lavage (BAL) fluids and peribronchial and perivascular tissues when compared with the Control-Asthma group. The Lvn-Asthma group also had less mucin hyperplasia than the Control-Asthma group. Furthermore, the Lvn-Asthma group showed lower interleukin (IL)-5 and IL-13 cytokine levels in BAL fluids, as well as reduced IL-4 and IL-5 mRNA expression in lung tissue, compared with the Control-Asthma group and determined by FlowCytomix and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. In addition, Lvn inhalation reduced Muc5b mRNA expression in the lungs without significantly changing the expression of Muc5ac mRNA. SIGNIFICANCE: Lvn inhibits allergic inflammation and mucous cell hyperplasia with suppression of T-helper-2 cell cytokines and Muc5b expression in a murine model of asthma. Consequently, Lvn may be useful as an alternative medicine for bronchial asthma.
Assuntos
Anti-Inflamatórios/farmacologia , Asma/tratamento farmacológico , Hiperplasia/tratamento farmacológico , Inflamação/tratamento farmacológico , Óleos Voláteis/farmacologia , Óleos de Plantas/farmacologia , Administração por Inalação , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Anti-Inflamatórios/administração & dosagem , Asma/imunologia , Asma/patologia , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Feminino , Inflamação/imunologia , Inflamação/patologia , Interleucina-13/metabolismo , Interleucina-5/metabolismo , Lavandula , Camundongos , Camundongos Endogâmicos BALB C , Mucina-5B/genética , Óleos Voláteis/administração & dosagem , Ovalbumina/imunologia , Óleos de Plantas/administração & dosagem , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Th2/imunologia , Fatores de TempoRESUMO
We studied the association of serum levels of arachidonic acid (AA) and eicosapentaenoic acid (EPA) with the prevalence of major adverse cardiac events (MACE) after acute myocardial infarction (AMI). We measured serum AA and EPA on admission in 146 consecutive AMI patients. The primary clinical endpoint was occurrence of MACE, defined as cardiac death, occurrence of heart failure, reinfarction, recurrent angina pectoris, and requirement of coronary intervention. Common logarithmic transformed serum levels of AA (logAA) and EPA (logEPA) were used in the analyses. The optimum cutoff point of each fatty acid used to distribute patients into two groups for Kaplan-Meier analysis was determined by receiver operating characteristic curves analysis. MACE occurred in 40 patients (27.4%). Kaplan-Meier analysis disclosed that the group with a logAA above the cutoff point [145.3 µg/mL (logAA 2.162)] showed a higher prevalence of MACE than those with a logAA below the cutoff point (P < 0.01). Conversely, the prevalence of MACE was significantly higher in the group with a logEPA below the cutoff point [52.3 µg/mL (logEPA 1.719)] compared to the group with a logEPA above it (P < 0.01). Similar to logAA, logAA/logEPA showed significant differences in the MACE-free curve between the two groups (cutoff 1.301, P < 0.001). Cox proportional hazards regression analysis suggested that logAA, logEPA, and logAA/logEPA were independently associated with the prevalence of MACE. Although the present study included a limited number of patients with single-time point measurement, the results suggested an association of logAA, logEPA, and logAA/logEPA with the prevalence of MACE after AMI. The present study warrants further studies involving a large number of patients to confirm that the serum levels of these fatty acids and their ratios are predictors of MACE after AMI.
Assuntos
Ácido Araquidônico/sangue , Ácido Eicosapentaenoico/sangue , Cardiopatias/sangue , Infarto do Miocárdio/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Angiografia Coronária , Feminino , Cardiopatias/diagnóstico por imagem , Cardiopatias/epidemiologia , Cardiopatias/mortalidade , Humanos , Japão/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/mortalidade , Valor Preditivo dos Testes , Prevalência , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
Connective tissue growth factor (CTGF) is a secreted protein that regulates fibrosis. We hypothesized that CTGF is induced in a pressure-overloaded (PO) heart and that blocking the angiotensin II type 1 receptor would reduce CTGF expression. Accordingly, we administered olmesartan and compared its effects with other antihypertensive drugs in a PO heart. CTGF induction was determined in a rat PO model, and olmesartan, hydralazine or saline was continuously administered. The effects of olmesartan on CTGF induction, myocyte hypertrophy and fibrosis were evaluated. The effect of olmesartan on cardiac function was also examined in CTGF- and transforming growth factor-beta 1 (TGF-ß1)-infused rats. CTGF was increased in the PO heart 3 days after aortic banding and was markedly distributed around the perivascular fibrotic area. After 28 days, blood pressure was not significantly different in the olmesartan and hydralazine groups, but olmesartan treatment reduced CTGF distribution in PO hearts. Olmesartan was associated with a significantly reduced myocyte hypertrophy index (4.77±0.48 for olmesartan and 6.05±1.45 for saline, P<0.01), fibrosis area (32.0±15.5% compared with the saline group, P<0.05) and serum TGF-ß1 level (62.6±10.6 ng ml⻹ for olmesartan and 84.4±7.2 ng ml⻹ for hydralazine, P<0.05). In addition, cardiac function was significantly preserved in the olmesartan group compared with the saline group. Finally, olmesartan ameliorated the cardiac dysfunction in CTGF- and TGF-ß1-infused rats. Olmesartan attenuated CTGF induction, reduced perivascular fibrosis and ameliorated cardiac dysfunction in a PO heart. Our results provide insight into the beneficial effects of olmesartan on PO hearts, independent of blood-pressure lowering.
Assuntos
Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Coração/efeitos dos fármacos , Imidazóis/farmacologia , Miocárdio/metabolismo , Tetrazóis/farmacologia , Análise de Variância , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Cardiomegalia/patologia , Fator de Crescimento do Tecido Conjuntivo/administração & dosagem , Fator de Crescimento do Tecido Conjuntivo/genética , Ecocardiografia , Ensaio de Imunoadsorção Enzimática , Fibrose , Hidralazina/farmacologia , Hidralazina/uso terapêutico , Imidazóis/uso terapêutico , Imuno-Histoquímica , Masculino , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tetrazóis/uso terapêutico , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
OBJECTIVES: Based on well-established physiological theories, we studied correlations between changes in brachial-ankle pulse wave velocity (baPWV) relative to blood pressure (BP) elevation (elasticity of large-to-medium-sized arteries), and coronary artery disease (CAD). METHODS: The baPWV (in centimeters/second) and BP (in millimeters of mercury) were determined in 101 patients before, during, and/or after a cold pressor test using a volume-plethysmographic system. RESULTS: Significantly higher rates of increase in PWV relative to changes in BP were observed in the CAD(+) group than in the CAD(-) group when mean BP [median (25th-75th percentiles): 14.8 (8.3-24.9) vs. 8.6 (5.7-11.4) cm/s/mmHg, P<0.0001], and systolic [10.1 (6.0-17.5) vs. 6.4 (4.4-10.6) cm/s/mmHg, P=0.0023] and diastolic BP [21.0 (14.0-34.4) vs. 10.8 (6.8-16.1) cm/s/mmHg, P<0.0001] were used as BP indices. Similarly, the rates of increase in baPWV showed a significant correlation with the extent of CAD. The rate of increase in baPWV obtained using the mean, systolic and diastolic BP as indices showed an area under the receiver operating characteristic curve of 0.68-0.76, sensitivity of 65-75%, and specificity of 65-75% for the detection of CAD. The area under the receiver operating characteristic curve, sensitivity, and specificity for the rate of increase were slightly higher than those for baseline baPWV and baseline baPWV/baseline BP ratio, but not to a significant degree. CONCLUSION: The rate of increase in baPWV relative to BP elevation determined by cold pressor test is significantly and moderately correlated with CAD. To identify patients with CAD, the rate of increase in baPWV relative to changes in BP can provide considerable, but limited, information.
Assuntos
Índice Tornozelo-Braço , Doença da Artéria Coronariana , Resistência Vascular , Adulto , Idoso , Artérias/patologia , Artérias/efeitos da radiação , Velocidade do Fluxo Sanguíneo/efeitos da radiação , Pressão Sanguínea/efeitos da radiação , Resposta ao Choque Frio , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/fisiopatologia , Elasticidade/efeitos da radiação , Feminino , Humanos , Hipotermia Induzida/métodos , Japão , Masculino , Pessoa de Meia-Idade , Pletismografia/métodos , Valor Preditivo dos Testes , Resistência Vascular/efeitos da radiaçãoRESUMO
OBJECTIVES: The relationships between filtered QRS duration and ventricular dyssynchrony were studied. METHODS: We measured filtered QRS duration on signal-averaged electrocardiography and analyzed tissue Doppler imaging in chronic heart failure patients with ejection fraction less than 50%. RESULTS: In 64 patients, interventricular and intraventricular dyssynchronies were observed in 25 and 38 patients, respectively. All patients with interventricular dyssynchrony were associated with intraventricular dyssynchrony. Filtered QRS showed 0.82 and 0.78 of the area under the curve (AUC) in the receiver operating characteristic curve (ROC) for the detection of interventricular and intraventricular dyssynchrony, respectively, with 89.7% and 96.2% specificity and 52.0% and 52.6% sensitivity, with cutoff values of 174 and 153 milliseconds. Specificity and sensitivity as well as AUC were lower in the ROC of QRS duration than filtered QRS duration. CONCLUSION: Filtered QRS duration provided more reliable information to estimate ventricular dyssynchrony in patients with reduced ventricular ejection fraction than QRS duration did.
Assuntos
Algoritmos , Diagnóstico por Computador/métodos , Ecocardiografia/métodos , Técnicas de Imagem por Elasticidade/métodos , Processamento de Sinais Assistido por Computador , Volume Sistólico , Disfunção Ventricular Esquerda/diagnóstico , Idoso , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estatística como AssuntoRESUMO
ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is an inflammatory-induced gene. We have previously reported that ADAMTS1 was strongly but transiently expressed in the infarcted heart. In this study, we investigated whether a 3'-untranslated region (UTR) affects the mRNA stability of this gene. When stimulated with tissue necrosis factor (TNF)-alpha, the expression level of ADAMTS1 mRNA rapidly increased, but the induction of ADAMTS1 mRNA peaked at 6h after stimulation, after which the expression levels of ADAMTS1 mRNA decreased. The 3'-UTR ADAMTS1 mRNA contains multiple adenine and uridine-rich elements, suggesting that the 3'-UTR may regulate gene stability. The addition of actinomycin D, an RNA synthesis inhibitor, demonstrated the decay of induced ADAMTS1 mRNA by TNF-alpha. Furthermore, a region containing multiple AUUUA motifs within the ADAMTS1 3'-UTR destabilized transfected Enhanced Green Fluorescence Protein (EGFP) mRNA expression. These results demonstrated that the ADAMTS1 3'-UTR may regulate the expression of ADAMTS1 mRNA.
Assuntos
Regiões 3' não Traduzidas/genética , Proteínas ADAM , Estabilidade de RNA/genética , RNA Mensageiro , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Proteína ADAMTS1 , Animais , Sequência de Bases , Células COS , Chlorocebus aethiops , Dactinomicina/metabolismo , Humanos , Camundongos , Dados de Sequência Molecular , Inibidores da Síntese de Ácido Nucleico/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is a member of the matrix metalloproteinase family. We have previously reported that ADAMTS1 was strongly expressed in myocardial infarction. In this study, we investigated whether hypoxia induced ADAMTS1 and investigated its regulatory mechanism. In hypoxia, the expression level of ADAMTS1 mRNA and protein rapidly increased in endothelial cells, but not in other cell types. Interestingly, the induction of ADAMTS1 by hypoxia was transient, whereas vascular endothelial growth factor induction by hypoxia in human umbilical vein endothelial cells (HUVEC) increased in a time-dependent manner. CoCl2, a transition metal that mimics hypoxia, induced ADAMTS1 in HUVEC. The phosphatidylinositol 3-kinase inhibitor LY294002 dose-dependently inhibited the increase of ADAMTS1 mRNA expression in hypoxia. We characterized the promoter region of ADAMTS1, and the secreted luciferase assay system demonstrated that hypoxia induced luciferase secretion in the culture medium 4.6-fold in HUVEC. In the promoter region of ADAMTS1, we found at least three putative hypoxia-inducible factor (HIF) binding sites, and the chromatin immunoprecipitation assay revealed HIF-1 binding to HIF binding sites in the promoter region of ADAMTS1 under hypoxia. Recombinant ADAMTS1 protein promoted the migration of HUVEC under hypoxic conditions. In summary, we found that ADAMTS1 is transiently induced by hypoxia in endothelial cells, and its transcription is mediated by HIF-1 binding. Our data indicate that ADAMTS1 is a novel acute hypoxia-inducible gene.
Assuntos
Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Células Endoteliais/fisiologia , Hipóxia/fisiopatologia , Proteína ADAMTS1 , Divisão Celular/fisiologia , Movimento Celular/fisiologia , Cromonas/farmacologia , Células Endoteliais/citologia , Inibidores Enzimáticos/farmacologia , Expressão Gênica/fisiologia , Humanos , Fator 1 Induzível por Hipóxia/metabolismo , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Regiões Promotoras Genéticas/fisiologia , Artéria Pulmonar/citologia , Ativação Transcricional/fisiologia , Veias Umbilicais/citologia , Regulação para Cima/fisiologiaRESUMO
During inflammation, lower molecular weight fragments of hyaluronan accumulate, and this is known to be inflammatory and immune-stimulatory. In diseases such as inflammatory bowel disease, inflammatory cells bind to hyaluronan; however, the cellular response and molecular mechanism of hyaluronan-hyaluronan receptor interactions in mononuclear cells are not well understood. The expression of hyaluronan receptors in peripheral blood mononuclear cells (PBMC) was examined. PBMC were stimulated with lower and higher molecular weight hyaluronan (molecular weight 100-150 kDa and 2700 kDa) and the induction of proinflammatory cytokines (interleukin-6 (IL-6) and monocyte chemoattractant protein (MCP-1)) was compared by enzyme-linked immunoabsorbant assay (ELISA). Cells were coincubated with various signaling pathway inhibitors. In addition, neutralizing antibodies against CD44 and TLR4 were added and the effects on PBMC were investigated. Finally, mononuclear cells from CD44-null and toll-like receptor 4 (TLR4) mutant mice were both stimulated with lower molecular weight hyaluronan. Among the hyaluronan receptors, TLR4 and CD44 were markedly expressed on PBMC. Hyaluronan-stimulated PBMC enhanced the attachment to the extracellular matrix. Lower molecular weight hyaluronan induced IL-6 and MCP-1 production in PBMC, but high-molecular-weight hyaluronan did not induce IL-6 and MCP-1 production. An anti-CD44 antibody attenuated the induction of both IL-6 and MCP-1 in lower molecular weight hyaluronan-stimulated PBMC. In both TLR4 mutant and CD44-null mice, the induction of IL-6 by lower molecular weight hyaluronan stimulation was decreased. SB203580 completely abolished IL-6 production in both TLR4 mutant and CD44-null mononuclear cells, while PD98059 abolished IL-6 production in CD44-null mononuclear cells. Hyaluronan receptors, CD44 and TLR4, play distinct roles in cytokine induction in hyaluronan-stimulated mononuclear cells.
Assuntos
Citocinas/metabolismo , Receptores de Hialuronatos/metabolismo , Monócitos/imunologia , Animais , Humanos , Receptores de Hialuronatos/análise , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Monócitos/citologia , Fosforilação , Transdução de SinaisRESUMO
BACKGROUND: The relationship between serum fatty acid levels and the extent of coronary plaques and calcification was examined in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: The serum levels of the n-3 polyunsaturated fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) and the n-6 polyunsaturated fatty acids (arachidonic acid (AA) and dihomo-gamma-linolenic acid (DGLA)) were determined using gas chromatography on admission of 95 consecutive patients with their first AMI and 17 controls. Using multidetector-row computed tomography, soft plaques and calcification lesions were scored according to the extent of coronary involvement. Serum logarithmic transformed (log) EPA and logDHA levels were inversely correlated with soft plaque scores (r=-0.546, p<0.0001 and r=-0.377, p<0.0001, respectively). Serum logAA and logDGLA levels were not significantly correlated with soft plaque scores. Serum logEPA and logDHA levels were significantly, but weakly, correlated with calcification scores. Multivariate analysis with clinical characteristics and risk factors selected serum n-3 polyunsaturated fatty acid levels as independent factors associated with the extent of coronary soft plaques. CONCLUSION: The present study demonstrates a significant correlation between serum n-3 polyunsaturated fatty acid levels and the extent of coronary soft plaques and calcification in AMI patients.
Assuntos
Calcinose/sangue , Doença da Artéria Coronariana/sangue , Ácidos Graxos Insaturados/sangue , Infarto do Miocárdio/sangue , Idoso , Calcinose/diagnóstico por imagem , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
We examined the hemodynamic responses to exercise and symptoms in 37 male patients with untreated essential hypertension, and compared the findings with those in 32 age-matched healthy male volunteers by performing a graded symptom-limited exercise test using a bicycle ergometer. The subjective feeling of intensity of exercise was determined using the Borg scale. In the relationship between Borg scores and blood pressure (BP), patients with hypertension showed higher systolic BP and diastolic BP relative to the Borg scores than the controls. Consequently, patients with hypertension showed significantly higher systolic BP with Borg scores < or = 3 (subjective symptoms < or = moderately hard) than the controls (177.8 +/- 27.0 vs. 143.7 +/- 17.9 mmHg, p < 0.0001). Similarly, significantly higher diastolic BP with Borg scores < or = 3 was observed in patients with hypertension than in the controls (101.6 +/- 12.0 vs. 82.6 +/- 11.6 mmHg, p < 0.0001). The pulse pressure with Borg scores < or = 3 was also significantly higher in patients with hypertension than in the controls (76.2 +/- 20.6 vs. 61.0 +/- 13.6 mmHg, p < 0.0001). Hypertensive patients showed a decrease in the high-frequency power of heart rate variability at initial low-load exercise. In conclusion, the present study revealed that there was a greater BP response relative to the Borg score in patients with hypertension than in the controls. Autonomic nerve activity may contribute to some extent to these different relations. A determination of the relationship between the subjective feeling of intensity of the exercise and BP levels caused by a given intensity of load is essential before exercise training in patients, at least in males, with hypertension to avoid increasing the risk of cardiovascular events in association with excessive exercise training.
Assuntos
Pressão Sanguínea , Exercício Físico , Hipertensão/fisiopatologia , Hipertensão/psicologia , Teste de Esforço , Frequência Cardíaca , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Psicofísica/métodos , Autoavaliação (Psicologia)RESUMO
OBJECTIVES: Minor cardiac biomarker elevation after percutaneous coronary intervention has long-term prognostic significance. The sirolimus-eluting stent (Cypher) has been reported to require high postinflation pressure for optimal implantation. We examined the incidence of minor cardiac biomarker elevation induced by Cypher implantation. METHODS: We measured the serum concentration of cardiac troponin-I (cTnI) 24 h after stenting and those of creatine kinase isoenzyme MB and creatine kinase before, immediately after, and 6, 12 and 24 h after implantation in patients who underwent Cypher stent (CS group; n=53) or bare metal stent (BMS group; n=57) implantation. RESULTS: No significant difference in clinical background was observed between the two groups. When a cutoff cTnI value of 0.50 ng/ml was used, the CS group showed a significantly higher incidence of cTnI elevation (35.8%, 19/53) than the BMS group (14.0%, 8/57) (P<0.05). Similarly, the incidence of cTnI > or = 0.03 ng/ml tended to be higher in the CS group (88.7%, 47/53) than in the BMS group (73.7%, 42/57: 0.05
Assuntos
Cateterismo/efeitos adversos , Creatina Quinase Forma MB/sangue , Stents Farmacológicos/efeitos adversos , Imunossupressores/efeitos adversos , Sirolimo/efeitos adversos , Troponina I/sangue , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: The augmentation index of the radial pulse wave has been reported to be a sensitive aortic stiffness marker in relatively young but not in older individuals. We studied the relationship between augmentation index and the diurnal blood pressure profiles. PATIENTS AND METHODS: Twenty-four-hour ambulatory blood pressure monitoring was performed in 90 untreated patients with uncomplicated essential hypertension. The patients were classified into four groups: dippers, extreme dippers, nondippers, and risers. Augmentation index was calculated as the percentage of the second systolic peak relative to the first systolic peak. RESULTS: No significant differences in the averaged whole 24-h systolic or diastolic blood pressure were observed in the whole set of patients or in subgroup patients with age 60 years or under. In the whole set of patients (58.7 +/- 12.9 years), there were significant differences in augmentation index between patients with abnormal (other than dippers) and normal diurnal blood pressure profiles (dippers). In subgroup patients with age 60 years or below (49.1 +/- 9.1 years, n = 48), the abnormal diurnal blood pressure profile group showed significantly higher augmentation index (89.6 +/- 10.3%) than dippers (80.5 +/- 11.8%). The area under the curve in the receiver operating characteristics curve for distinguishing between dippers than other dippers was 0.73 (P < 0.01). Multivariate analysis demonstrated that abnormal diurnal blood pressure profile was independently associated with increase in augmentation index. In contrast, these relationships were not significant in the over 60 years subgroup patients (69.8 +/- 5.6 years old, n = 42). CONCLUSIONS: The present study revealed that augmentation index was associated with dipping blood pressure patterns in untreated hypertensive patients aged 60 years or younger. Augmentation index determination would be useful for initial assessment in connection with possible abnormal diurnal blood pressure variability in patients with age 60 years or younger.
Assuntos
Pressão Sanguínea/fisiologia , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Artéria Radial/fisiopatologia , Área Sob a Curva , Ritmo Circadiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Ambulatorial , Sensibilidade e EspecificidadeRESUMO
OBJECTIVES: We examined the serum levels of interferon-gamma-inducible protein 10 (IP-10), an inflammation-induced chemokine, in acute myocardial infarction (AMI). DESIGN AND METHODS: The subjects were 33 AMI patients, 20 stable angina pectoris patients (AP) and 20 normal subjects. In AMI patients, blood samples were collected before percutaneous coronary intervention (PCI) and on days 3, 7 and 28. RESULTS: Patients with AMI showed significantly higher serum IP-10 levels (137.5+/-79.8 pg/mL) than control subjects (91.2+/-40.1 pg/mL) and patients with AP (93.3+/-41.1 pg/mL). The serum IP-10 level before PCI was negatively correlated with infarct size, as indicated by cumulative release of creatine kinase (CK) and peak CK and its isoenzyme CK-MB. Stepwise multiple regression analysis revealed that the serum IP-10 level before PCI was an independent predictor of cumulative CK release. CONCLUSIONS: The serum IP-10 level was increased in AMI, and a higher level of serum IP-10 before PCI may be informative regarding infarct size.
Assuntos
Quimiocina CXCL10/sangue , Infarto do Miocárdio/sangue , Infarto do Miocárdio/patologia , Idoso , Estudos de Casos e Controles , Angiografia Coronária , Creatina Quinase/sangue , Creatina Quinase Forma MB/sangue , Progressão da Doença , Feminino , Ventrículos do Coração/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Função Ventricular EsquerdaRESUMO
OBJECTIVES: To investigate the relationship between the plasma B-type natriuretic peptide (BNP) level and the occurrence of atrial fibrillation (AF) in nonobstructive hypertrophic cardiomyopathy (HCM) patients. METHODS: Patients (n=97) were classified into chronic AF (CAF; n=14), paroxysmal AF (PAF; n=18) and normal sinus rhythm (NSR; n=65) groups. The plasma BNP values were analyzed with logarithmic transformation. RESULTS: The PAF group showed significantly higher plasma BNP levels than the NSR group [mean (range; -l SD and +1 SD); 248.3 (143.5, 429.5) vs. 78.2 (27.9, 218.8 ng/L), p<0.0001]. The CAF group also showed significantly higher plasma BNP levels than the NSR group [291.1 (161.4, 524.8 ng/L), p<0.0001]. Multivariate analysis with other clinical factors selected association of PAF as one of the factors that increased the plasma BNP level. CONCLUSIONS: The present study indicated that plasma BNP level is clinically useful for identification of nonobstructive HCM patients who have a risk of PAF.