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INTRODUCTION: n-3 Polyunsaturated fatty acids such as eicosapentaenoic acid (EPA), which are abundant in fish oil, have been shown to delay the onset of cardiovascular events. We previously established DahlS.Z-Leprfa/Leprfa (DS/obese) rats, which are derived from a cross between Dahl salt-sensitive and Zucker rats, as a model of metabolic syndrome. This study has now explored the influence of highly purified EPA on cardiac and adipose tissue pathophysiology in this animal model. MATERIALS AND METHODS: DS/obese rats were administered EPA (300 or 1,000 mg kg-1 d-1, per os) or vehicle from age 9 to 13 weeks. Homozygous lean (DahlS.Z-Lepr+/Lepr+, or DS/lean) littermates were studied as controls. RESULTS: Whereas EPA had no effect on body weight, food intake or systolic blood pressure in DS/obese rats, it attenuated cardiac fibrosis, diastolic dysfunction, oxidative stress and inflammation in these animals. In addition, EPA did not affect insulin resistance but reduced adipocyte hypertrophy and inflammation in visceral fat of DS/obese rats. Moreover, EPA increased circulating levels of adiponectin as well as attenuated both the down-regulation of AMP-activated protein kinase phosphorylation and the up-regulation of phosphorylation of the p65 subunit of nuclear factor-kB in the heart of DS/obese rats. CONCLUSIONS: Treatment of DS/obese rats with EPA did not affect hypertension but reduced cardiac fibrosis and diastolic dysfunction, with the latter effects being accompanied by AMP-activated protein kinase activation and inactivation of nuclear factor-kB signalling in the heart, possibly as a result of an increase in adiponectin secretion. EPA may be suitable for the treatment of cardiac injury associated with metabolic syndrome.
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OBJECTIVES: Chronic stress affects the central nervous system as well as endocrine, metabolic and immune systems. However, the effects of cold stress on cardiovascular and metabolic disorders in metabolic syndrome (MetS) have remained unclear. We recently characterized DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of MetS. We have now investigated the effects of chronic cold stress and glucocorticoid receptor (GR) blockade on cardiac and adipose tissue pathology as well as on metabolic parameters in this model. METHODS: DS/obese rats were exposed to cold stress (immersion in ice-cold water to a depth of 1-2 cm for 2 h per day) with or without subcutaneous injection of the GR antagonist RU486 (2 mg kg(-1)day(-1)) for 4 weeks beginning at 9 weeks of age. Age-matched homozygous lean (DahlS.Z-Lepr(+)/Lepr(+)) littermates served as a control. RESULTS: Chronic cold stress exacerbated hypertension as well as left ventricular (LV) hypertrophy, fibrosis and diastolic dysfunction in DS/obese rats in a manner sensitive to RU486 treatment. Cold stress with or without RU486 did not affect body weight or fat mass. In contrast, cold stress further increased cardiac oxidative stress as well as macrophage infiltration and proinflammatory gene expression in LV and visceral fat tissue, with all of these effects being attenuated by RU486. Cold stress also further increased GR and 11ß-hydroxysteroid dehydrogenase type 1 mRNA and protein abundance in LV and visceral adipose tissue, and these effects were again inhibited by RU486. In addition, RU486 ameliorated the stress-induced aggravation of dyslipidemia, glucose intolerance and insulin resistance in DS/obese rats. CONCLUSIONS: Our results implicate GR signaling in cold stress-induced exacerbation of cardiac and adipose tissue pathology as well as of abnormal glucose and lipid metabolism in a rat model of MetS.
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Tejido Adiposo/efectos de los fármacos , Frío , Corazón/efectos de los fármacos , Mifepristona/farmacología , Receptores de Glucocorticoides/antagonistas & inhibidores , Estrés Fisiológico/efectos de los fármacos , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Tejido Adiposo/patología , Animales , Modelos Animales de Enfermedad , Fibrosis/tratamiento farmacológico , Intolerancia a la Glucosa , Corazón/fisiopatología , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/metabolismo , Masculino , Síndrome Metabólico/tratamiento farmacológico , Ratas , Ratas Endogámicas Dahl , Ratas Zucker , Receptores de Glucocorticoides/metabolismo , Receptores de Leptina/metabolismoRESUMEN
Obesity-related disorders are closely associated with the development of age-related hearing impairment (ARHI). Adiponectin (APN) exerts protective effects against obesity-related conditions including endothelial dysfunction and atherosclerosis. Here, we investigated the impact of APN on ARHI. APN-knockout (APN-KO) mice developed exacerbation of hearing impairment, particularly in the high frequency range, compared with wild-type (WT) mice. Supplementation with APN prevented the hearing impairment in APN-KO mice. At 2 months of age, the cochlear blood flow and capillary density of the stria vascularis (SV) were significantly reduced in APN-KO mice as compared with WT mice. APN-KO mice also showed a significant increase in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells in the organ of Corti in the cochlea at 2 months of age. At the age of 6 months, hair cells were lost at the organ of Corti in APN-KO mice. In cultured auditory HEI-OC1 cells, APN reduced apoptotic activity under hypoxic conditions. Clinically, plasma APN levels were significantly lower in humans with ARHI. Multiple logistic regression analysis identified APN as a significant and independent predictor of ARHI. Our observations indicate that APN has an important role in preventing ARHI.
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Adiponectina/deficiencia , Envejecimiento/patología , Progresión de la Enfermedad , Pérdida Auditiva/metabolismo , Adiponectina/sangre , Adiponectina/metabolismo , Adiponectina/farmacología , Animales , Apoptosis/efectos de los fármacos , Umbral Auditivo/efectos de los fármacos , Capilares/patología , Línea Celular , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/patología , Pérdida Auditiva/sangre , Pérdida Auditiva/patología , Pérdida Auditiva/fisiopatología , Humanos , Masculino , Ratones Noqueados , Persona de Mediana Edad , Órgano Espiral/irrigación sanguínea , Órgano Espiral/efectos de los fármacos , Órgano Espiral/patología , Órgano Espiral/fisiopatología , Flujo Sanguíneo Regional/efectos de los fármacosRESUMEN
BACKGROUND: Mechanisms underlying coffee's beneficial actions against cardiovascular disease and glucose metabolism are not well understood. Little information is available regarding association between coffee consumption and adipocytokines. OBJECTIVE: We investigated potential associations between coffee consumption and adiponectin, leptin, markers for subclinical inflammation, glucose metabolism, lipids and liver enzymes. We then investigated whether adipocytokines played a role in the association between coffee consumption and these markers. DESIGN AND SUBJECTS: This is a cross-sectional study comprising 2554 male and 763 female Japanese workers. Potential relations between coffee consumption and adipocytokines or other markers were evaluated using a multiple linear regression model adjusted for confounding factors. We evaluated whether adiponectin and leptin partly explain the associations between coffee consumption and each marker by multiple mediation analysis. RESULTS: Coffee consumption showed significant positive associations with adiponectin and total and low-density lipoprotein cholesterol, and inverse associations with leptin, high sensitivity C-reactive protein (hs-CRP), triglycerides and liver enzymes (all P<0.05). An adjustment for adiponectin and leptin significantly attenuated the associations between coffee consumption and hs-CRP or triglycerides, but not for liver enzymes. No associations were observed between coffee consumption and glucose metabolism-related markers. CONCLUSION: Coffee consumption was associated with high adiponectin and low leptin levels. We speculated that adipocytokines mainly explain the associations of coffee consumption with lipids and hs-CRP. Factors other than adipocytokines may explain the association between coffee consumption and liver function.
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This review focuses on the recent findings that adiponectin plays a significant role of in cardiovascular diseases. Adipose tissue functions as an endocrine organ by secreting adipocytokines that can directly affect nearby or remote organs. Adiponectin is an adipocytokine whose concentration is down-regulated in subjects with obesity-related disorders. Low levels of circulating adiponectin appear to associate with the increased prevalence of obesity-linked diseases including atherosclerosis and ischemic heart disease. A number of experimental studies have shown that adiponectin exerts beneficial effects on the cardiovascular system by directly acting on the component cells in the heart and blood vessels. The cardiovascular protection by adiponectin is mediated through its ability to attenuate inflammatory responses and apoptotic activities in the target organs. Thus, adiponectin could represent a therapeutic target molecule for prevention or treatment of cardiovascular diseases.
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Adiponectina/metabolismo , Enfermedades Cardiovasculares/metabolismo , Animales , Vasos Sanguíneos/citología , Vasos Sanguíneos/metabolismo , Humanos , Miocardio/citología , Miocardio/metabolismo , Receptores de Adiponectina/metabolismoRESUMEN
AIMS/HYPOTHESIS: End-stage renal disease (ESRD) patients with diabetes have been regarded as being at the highest risk of cardiovascular disease. We therefore investigated the relationship between diabetes and the incidence of peripheral artery disease (PAD) in new haemodialysis patients. METHODS: We enrolled 1,513 ESRD patients who had just begun haemodialysis therapy. They were divided into two groups: those with (n = 739) and those without diabetes (n = 774). The endpoint was the development of PAD, defined as ankle brachial pressure index ≤ 0.9 or toe brachial pressure index <0.7 in patients with an ankle brachial pressure index >0.9. RESULTS: According to the Kaplan-Meier method, the 10 year event-free rate for development of PAD and lower limb amputation was significantly lower in the diabetes group than in the non-diabetes group (60.3% vs 82.8%, HR 2.99, 95% CI 2.27, 3.92, p<0.0001 and 93.9% vs 98.9%, HR 5.59, 95% CI 2.14, 14.7, p = .0005 for PAD and lower limb amputation, respectively). In patients with diabetes, quartile analysis of HbA1c levels showed that the highest quartile group (≥ 6.8% [51 mmol/mol]) had significant development of PAD and lower limb amputation compared with lower quartile groups (PAD HR 1.63, 95% CI 1.17, 2.28, p = .0038; lower limb amputation HR 2.99, 95% CI 1.17, 7.70, p = .023). CONCLUSIONS/INTERPRETATION: Diabetes was a strong predictor of PAD after initiation of haemodialysis therapy in patients with ESRD. In addition, higher HbA1c levels were associated with increased risk of developing PAD and requiring limb amputation in such diabetic populations.
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Complicaciones de la Diabetes/epidemiología , Diabetes Mellitus/epidemiología , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Enfermedad Arterial Periférica/etiología , Diálisis Renal/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Amputación Quirúrgica/estadística & datos numéricos , Pueblo Asiatico/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Hemoglobina Glucada/análisis , Humanos , Japón/epidemiología , Fallo Renal Crónico/epidemiología , Extremidad Inferior/cirugía , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/epidemiología , Resultado del TratamientoRESUMEN
BACKGROUND: Corrected QT (QTc) interval prolongation can induce fatal arrhythmias such as torsade de pointes. PATIENTS AND METHODS: To assess the characteristics of QTc intervals and arrhythmias in women with early breast cancer who received FEC100 adjuvant chemotherapy, electrocardiograms (ECGs) were recorded before and after each chemotherapy. Associations between QTc interval prolongation and single nucleotide polymorphisms (SNPs) of potassium channel genes were also investigated. RESULTS: A total of 131 ECG records were obtained in 34 patients who received 153 cycles of FEC100. QTc intervals could be measured in 127 records. There was a significant trend toward QTc interval prolongation after each treatment, persisting through four cycles of chemotherapy (P < 0.001). Median QTc interval prolongations were 13, 11, 18, and 14 ms in the first through fourth cycles of chemotherapy, respectively. QTc intervals differed significantly between cycles 1 and 4 before treatment as well as after treatment (P < 0.05). A single supraventricular premature contraction was noted in 3 (2.3%) of the 131 cycles in 2 (5.9%) of the 34 patients. There was no significant association between QTc interval prolongation and SNPs of potassium channel genes. CONCLUSION: This prospective study confirmed that FEC100 is associated with significant QTc interval prolongation in women with early breast cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Arritmias Cardíacas/inducido químicamente , Neoplasias de la Mama/tratamiento farmacológico , Corazón/efectos de los fármacos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Arritmias Cardíacas/epidemiología , Quimioterapia Adyuvante/efectos adversos , Electrocardiografía , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , Canales de Potasio/genética , Estudios Prospectivos , Adulto JovenRESUMEN
OBJECTIVES: Cilostazol is known to be a selective inhibitor of phosphodiesterase 3 and is generally used to treat intermittent claudication caused by peripheral arterial disease. However, there is little information concerning the effect of cilostazol on angiogenesis. Here, we investigated whether cilostazol modulates the angiogenic process in vivo employing a hindlimb model of ischaemia-induced angiogenesis. DESIGN: This was an experimental study. MATERIALS AND METHODS: Wild-type (WT) mice were randomly divided into two groups and were treated with or without cilostazol. One week later, the mice were subjected to unilateral hindlimb ischaemia. Angiogenesis was determined by laser Doppler analysis and capillary density stained with CD31. The expression of endothelial nitric oxide synthase (eNOS) was assessed by immunoblotting. RESULTS: WT mice treated with cilostazol showed accelerated neo-vascularisation following hindlimb ischaemic surgery on post-operative day 14 based upon laser Doppler measurements of blood flow (cilostazol-treated group, 0.54 ± 0.13 vs. control group, 0.38 ± 0.11; P-<-0.05). The capillary density in the ischaemic hindlimb was also significantly greater in WT mice treated with cilostazol than in non-treated WT mice (cilostazol-treated group, 1.63 ± 0.10 vs. control group, 1.15 ± 0.12; P-<-0.01). Cilostazol stimulated an ischaemia-induced increase in the phosphorylation of eNOS in the ischaemic limbs. Administration of NOS inhibitor N-nitro-l-arginine methyl ester (l-NAME) abolished cilostazol-induced increase in limb perfusion. CONCLUSIONS: Our observations indicate that cilostazol can promote neo-vascularisation in response to tissue ischaemia via an eNOS-dependent mechanism. Cilostazol could be useful for treatment of ischaemic limb diseases.
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Inductores de la Angiogénesis/farmacología , Capilares/efectos de los fármacos , Isquemia/tratamiento farmacológico , Músculo Esquelético/irrigación sanguínea , Neovascularización Fisiológica/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Inhibidores de Fosfodiesterasa 3/farmacología , Tetrazoles/farmacología , Animales , Western Blotting , Capilares/enzimología , Capilares/fisiopatología , Cilostazol , Modelos Animales de Enfermedad , Miembro Posterior , Inmunohistoquímica , Isquemia/enzimología , Isquemia/fisiopatología , Flujometría por Láser-Doppler , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/deficiencia , Óxido Nítrico Sintasa de Tipo III/genética , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Factores de TiempoRESUMEN
AIMS: We previously showed that the CâT polymorphism (rs6929846) of BTN2A1 was significantly associated with myocardial infarction in Japanese individuals by a genome-wide association study. Given that diabetes mellitus is an important risk factor for myocardial infarction, the association of rs6929846 of BTN2A1 with myocardial infarction might be attributable, at least in part, to its effect on susceptibility to diabetes. The purpose of this study was to examine the relation of rs6929846 of BTN2A1 to Type 2 diabetes mellitus. METHODS: A total of 8650 Japanese individuals from two independent subject panels were examined: Panel A comprised 1141 individuals with Type 2 diabetes and 3161 control subjects and panel B comprised 1664 individuals with Type 2 diabetes and 2684 control subjects. RESULTS: The chi-square test revealed that rs6929846 of BTN2A1 was significantly related to the prevalence of Type 2 diabetes in subject panel A (P = 0.0002) and subject panel B (P=0.006). Multivariable logistic regression analysis with adjustment for age, sex, body mass index and smoking status revealed that rs6929846 was significantly associated with Type 2 diabetes (P = 0.0006; odds ratio 1.25) in all individuals, with the T allele representing a risk factor for this condition. Multiple regression analysis with adjustment for age, sex and body mass index revealed that rs6929846 was significantly (P=0.04) related to blood glycosylated haemoglobin content in control subjects. CONCLUSIONS: BTN2A1 may be a susceptibility gene for Type 2 diabetes in Japanese individuals.
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Pueblo Asiatico/genética , Diabetes Mellitus Tipo 2/genética , Glicoproteínas de Membrana/genética , Infarto del Miocardio/genética , Polimorfismo de Nucleótido Simple , Anciano , Índice de Masa Corporal , Butirofilinas , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Modelos Logísticos , Masculino , Análisis Multivariante , Infarto del Miocardio/epidemiología , Infarto del Miocardio/etiología , Oportunidad Relativa , Análisis de Regresión , Factores de RiesgoRESUMEN
In this study, we report the comparative result of long-term clinical prognoses for patients with no-option critical limb ischemia (CLI) caused by arteriosclerosis obliterans, who are implanted with autologous bone marrow mononuclear cells (BMMNC; n=74) or G-CSF-mobilized (M)-PBMNC (n=111), as no information is available on how the two treatments compare in terms of long-term prognosis, such as survival or amputation. We performed pooled analysis using data from two previous cohort studies. All patients had disease of Fontaine classification III or IV. The endpoints were OS and amputation-free survival (AFS). After adjustment for history of dialysis and Fontaine classification, there was no significant difference between the two treatments with respect to OS (hazard ratio (HR)=1.49; 95% confidence interval (CI)=0.74-3.03, P=0.26) or AFS (HR=0.96; 95% CI=0.61-1.51, P=0.87). The negative prognostic factors affecting OS or AFS were the small number of CD34-positive cells collected, history of dialysis, Fontaine classification, male sex and older age. These results suggest that there was no significant difference in long-term prognosis between patients treated with BMMNC and those treated with M-PBMNC. The number of CD34-positive cells collected was an important prognostic factor for amputation and death.
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Arteriosclerosis Obliterante/cirugía , Trasplante de Médula Ósea , Factor Estimulante de Colonias de Granulocitos/farmacología , Movilización de Célula Madre Hematopoyética/métodos , Leucocitos Mononucleares/trasplante , Trasplante de Células Madre de Sangre Periférica , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD34/análisis , Arteriosclerosis Obliterante/mortalidad , Femenino , Humanos , Extremidad Inferior , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
OBJECTIVE: The DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rat strain was established from a cross between Dahl salt-sensitive rats and Zucker fatty (fa/fa) rats, the latter of which harbor a missense mutation in the leptin receptor gene (Lepr). We examined whether DS/obese rats might be a suitable animal model of metabolic syndrome in humans. METHODS: The systemic pathophysiological and metabolic characteristics of DS/obese rats were determined and compared with those of homozygous lean littermates, namely, DahlS.Z-Lepr(+)/Lepr(+) (DS/lean) rats. RESULTS: Systolic blood pressure was higher in DS/obese rats fed a normal diet than in DS/lean rats at 11 weeks of age and thereafter. The survival rate of DS/obese rats was significantly lower than that of DS/lean rats at 18 weeks. Body weight, visceral and subcutaneous fat mass, as well as heart, kidney and liver weights, were increased in DS/obese rats at 18 weeks compared with DS/lean rats. Serum low-density lipoprotein (LDL)-cholesterol, triglyceride and insulin concentrations, as well as the ratio of LDL-cholesterol to high-density lipoprotein-cholesterol levels, were increased in DS/obese rats, whereas serum glucose concentration did not differ significantly between DS/obese and DS/lean rats. Creatinine clearance was decreased and urinary protein content was increased in DS/obese rats, which also manifested lipid accumulation in the liver and elevation of serum alanine aminotransferase levels. CONCLUSION: These results show that the phenotype of DS/obese rats is similar to that of humans with metabolic syndrome, and that these animals may thus be an appropriate model for this condition.
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AIMS/HYPOTHESIS: Resistin is a cytokine derived from adipose tissue and is implicated in obesity-related insulin resistance and type 2 diabetes mellitus. Polymorphisms of the resistin gene (RETN) have been shown to affect the plasma resistin concentration. The aims of this study were to identify polymorphisms of RETN that influence plasma resistin concentration and to clarify the relation between plasma resistin level and metabolic disorders in an aged Japanese cohort. METHODS: The study participants comprised 3133 individuals recruited to a population-based prospective cohort study (KING study). Plasma resistin concentration, BMI, abdominal circumference, blood pressure, fasting plasma glucose and serum insulin concentrations, HbA(1c) content and serum lipid profile were measured in all participants. The HOMA index of insulin resistance (HOMA-IR) was also calculated. Eleven polymorphisms of RETN were genotyped. RESULTS: A combination of ANOVA and multiple linear regression analysis in screening and large-scale subsets of the study population revealed that plasma resistin concentration was significantly associated with rs34861192 and rs3745368 polymorphisms of RETN. Multiple linear regression analysis with adjustment for age and sex also showed that the plasma resistin level was significantly associated with serum concentrations of HDL-cholesterol, triacylglycerol and insulin, as well as with BMI. CONCLUSIONS/INTERPRETATION: Our results implicate the rs34861192 and rs3745368 polymorphisms of RETN as robust and independent determinants of plasma resistin concentration in the study population. In addition, plasma resistin level was associated with dyslipidaemia, serum insulin concentration and obesity. TRIAL REGISTRATION: ClinicalTrials.gov NCT00262691.
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Variación Genética , Enfermedades Metabólicas/sangre , Resistina/sangre , Resistina/genética , Anciano , Análisis de Varianza , Glucemia/metabolismo , Presión Sanguínea , Índice de Masa Corporal , Tamaño Corporal , Estudios de Cohortes , Diabetes Mellitus Tipo 2/genética , Femenino , Genotipo , Hemoglobina Glucada/metabolismo , Humanos , Japón , Lípidos/sangre , Masculino , Enfermedades Metabólicas/genética , Persona de Mediana Edad , Análisis de RegresiónRESUMEN
An understanding of aminopeptidase A in hypertension is important, given its ability to cleave the N-terminal aspartic acid of potent vasoconstrictor angiotensin II. However, the role of aminopeptidase A in hypertension has received limited attention. Because we have succeeded in producing recombinant human aminopeptidase A, the effect of aminopeptidase A on systolic blood pressure in the spontaneously hypertensive rat was examined. Aminopeptidase A of 0.016 mg/kg was administrated intravenously to spontaneously hypertensive rats and blood pressure was monitored for 72 h. For repeated administration, aminopeptidase A doses of 0.016 mg/kg and 0.1-mg/kg doses of candesartan (an angiotensin II receptor 1 subtype blocker) were administrated daily in spontaneously hypertensive rats and blood pressure was monitored for 5 d. Bolus intravenous injection of aminopeptidase A at a dose of 0.016 mg/kg significantly decreased systolic blood pressure for 36 h in spontaneously hypertensive rats. A comparison of the antihypertensive effects of aminopeptidase A versus candesartan in spontaneously hypertensive rats showed that the effective dose of aminopeptidase A was about one-tenth that of candesartan. These results suggest the novel approach of utilizing aminopeptidase A to treat hypertension by degrading circulating angiotensin II before it binds to the receptor 1 subtype.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Antihipertensivos , Bencimidazoles/farmacología , Glutamil Aminopeptidasa/farmacología , Hipertensión/tratamiento farmacológico , Tetrazoles/farmacología , Angiotensina I/sangre , Angiotensina II/sangre , Animales , Baculoviridae/genética , Compuestos de Bifenilo , Presión Sanguínea/efectos de los fármacos , Vectores Genéticos , Glutamil Aminopeptidasa/genética , Humanos , Masculino , Mutación , Nitroprusiato/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Proteínas Recombinantes/farmacologíaRESUMEN
OBJECTIVE: To evaluate regional and global left ventricular (LV) function and LV wall thickness (LVWT) in patients with hypertrophic cardiomyopathy (HCM). DESIGN AND SETTING: Observational study at the National Cardiovascular Centre and Nagoya University Hospital in Japan. PARTICIPANTS: Thirty-six patients with HCM and 16 patients with hypertensive LV hypertrophy (LVH). MAIN OUTCOME MEASURES: Conventional echocardiography and strain rate (SR) imaging derived from tissue Doppler imaging were performed. Systolic strain (epsilon(sys)), peak systolic SR (SR(sys)), peak early diastolic SR (SR(dia)) and LVWT were obtained from eight LV segments. LV pressure was simultaneously recorded with a high-fidelity micromanometer. RESULTS: The regional epsilon(sys) and SR(sys) were correlated with LVWT in patients with HCM (r = 0.50, p<0.001 and r = 0.63, p<0.001, respectively) but not in patients with hypertensive LVH. The standard deviations of LVWT, epsilon(sys) and SR(sys) obtained from the eight LV segments of each subject were greater for patients with HCM than for patients with hypertensive LVH. The standard deviation of LVWT was correlated with those of epsilon(sys) and SR(sys) (r = 0.55, p<0.001 and r = 0.56, p<0.001, respectively). The standard deviations of LVWT, epsilon(sys) and SR(sys) were correlated with tau (r = 0.35, p<0.05; r = 0.47, p<0.001; and r = 0.39, p<0.005, respectively). CONCLUSIONS: Heterogeneity of regional LV systolic function detected by SR imaging is in part attributable to heterogeneity of LVH and may be linked to impaired global LV relaxation in HCM.
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Cardiomiopatía Hipertrófica/fisiopatología , Disfunción Ventricular Izquierda/fisiopatología , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Ecocardiografía Doppler , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sístole , Disfunción Ventricular Izquierda/diagnóstico por imagenRESUMEN
BACKGROUND: We previously reported that the targeted disruption of murine antithrombin (AT) gene resulted in embryonic lethality before 16.5 gestational days (gd) because of severe cardiac and hepatic thrombosis. OBJECTIVE AND METHODS: To investigate the influences of lowered tissue factor (TF) activity upon hypercoagulation of AT-/- embryos, we crossed AT+/- with low TF (mTF-/- hTF+) mice to yield homozygous AT-deficient mice with the extremely low TF activity, that is expressed from the inserted human TF mini gene. RESULTS: AT-/- embryos either with 50% TF (AT-/- mTF+/- hTF+) or with low (approximately 1% TF, AT-/- mTF-/- hTF+) were not born, although the survival was prolonged until 18.5 gd. In both genotypes, histological examination showed disseminated thrombosis in hepatic sinusoidal space or in the portal veins, suggesting that the thrombogenesis caused loss of hepatic blood flow. As in original AT-/-, AT-/- mTF+/- hTF+ showed subcutaneous (s.c.) bleeding and also suffered from the myocardial degeneration apparently because of coronary thrombus formation. However, AT-/- mTF-/- hTF+ had no skin hemorrhage and the thrombosis and degeneration were completely abolished in the heart. Myocardium of adult low TF mice had exhibited fibrosis secondary to hemorrhage; however, it was significantly decreased in low TF mice with AT+/-. CONCLUSIONS: Our current model suggests that, in the heart, TF plays an important role in the thrombogenesis and it counterbalances AT-dependent anticoagulation. AT may be a potent anticoagulant during mice development and the activation and subsequent regulation of TF-procoagulant activity take place differently between the liver and the heart. These differences appear to point to local regulatory mechanisms in murine hemostasis.
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Antitrombina III/fisiología , Tromboplastina/fisiología , Trombosis/etiología , Animales , Antitrombina III/genética , Síndrome de Budd-Chiari/sangre , Síndrome de Budd-Chiari/etiología , Trombosis Coronaria/sangre , Trombosis Coronaria/etiología , Embrión de Mamíferos , Hemorragia/etiología , Hemostasis , Humanos , Hígado/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Miocardio/metabolismo , Miocardio/patología , Tromboplastina/deficiencia , Trombosis/sangre , Trombosis/mortalidadRESUMEN
The two hypothalamic hormones, GH-releasing hormone (GHRH) and somatostatin (SRIF), are known to regulate GH secretion. However, the effects of these hormones on GH gene expression are not completely clear, partly because of the lack of appropriate host cells maintaining the original characteristics of the somatotroph. Since MtT/S, a pure somatotroph cell line, has become available, the effects of GHRH and SRIF on GH gene transcription have been studied using a subclone of MtT/S (MtT/SGL), in which the GH gene 5'-promoter-luciferase fusion gene was stably incorporated. The expression of GHRH receptor and SRIF receptor subtypes was also studied by RT-PCR. The results showed that MtT/SGL cells intrinsically expressed the functional GHRH receptor and all of the SRIF receptor subtypes. The expression of GHRH receptor was markedly enhanced by glucocorticoid pretreatment and, in the presence of corticosterone and 3-isobutyl-1-methylxanthine, GHRH (at or above 100 pM) stimulated GH gene 5'-promoter activity in a dose-dependent manner. On the other hand, SRIF (100 nM) significantly antagonized the effect of GHRH, which was completely reversed by pretreatment with pertussis toxin (50 ng/ml). Taken together, the present data indicated that both GHRH and SRIF are involved in the transcriptional regulation of the GH gene, and that the effect of SRIF is mediated through pertussis toxin-sensitive G protein. The MtT/SGL cell line is a good in vitro model for studying the molecular mechanisms of GH gene transcription by GHRH and/or SRIF.
Asunto(s)
Regulación de la Expresión Génica/efectos de los fármacos , Hormona Liberadora de Hormona del Crecimiento/farmacología , Hormona del Crecimiento/metabolismo , Receptores de Somatostatina/metabolismo , Somatostatina/farmacología , 1-Metil-3-Isobutilxantina/farmacología , Animales , Células Cultivadas , Corticosterona/farmacología , Proteínas de Unión al GTP/metabolismo , Genes Reporteros/genética , Hormona del Crecimiento/genética , Hormona Liberadora de Hormona del Crecimiento/genética , Toxina del Pertussis/farmacología , Regiones Promotoras Genéticas/genética , Ratas , Receptores de Neuropéptido/genética , Receptores de Neuropéptido/metabolismo , Receptores de Hormona Reguladora de Hormona Hipofisaria/genética , Receptores de Hormona Reguladora de Hormona Hipofisaria/metabolismo , Receptores de Somatostatina/genética , Somatostatina/genéticaRESUMEN
This study aimed to determine whether combined examinations of myocardial 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) and stress-redistribution 201Tl single-photon emission computed tomography (Tl SPECT) were useful in clarifying myocardial ischaemia and evaluating the prognosis in patients with idiopathic dilated cardiomyopathy (IDCM). Twenty-two patients with IDCM underwent echocardiography, cardiac catheterization, FDG PET, and Tl SPECT. In scintigraphic analysis, the total defect score (TDS) was semiquantitatively determined as the sum of scores of the 17 left ventricular (LV) segments with a 5-point scale (0 as normal to 4 as absent). Patients were classified according to the scintigraphic findings as follows: eight patients with small defects on Tl and FDG (TDS < or = 20) (group I), eight patients with small defects on FDG (TDS < or = 20) with FDG uptake increased relative to Tl or 'mismatch' (group II), and six patients with large defects on FDG and Tl (TDS >20) (group III). Eleven patients (50%) showed reversible defects on Tl and all showed preserved FDG uptake. The patients in group III had significantly lower LV ejection fraction (LVEF) (P<0.05, respectively) and a poorer prognosis as shown by the Kaplan-Meier event-free curve compared with those in groups I and II (P<0.01, respectively). Although patients in group II had significantly greater TDS on Tl compared with those in group I (P<0.01), no significant differences in LVEF and prognosis were found between patients in groups I and II. In multivariate analysis, a TDS on FDG revealed an independent predictor of subsequent cardiac events. In conclusion, such mismatched areas can be assumed to consist of impaired but viable myocardium, and may be associated with ischaemia of the microvasculature. Impaired myocardial glucose metabolism is a more powerful predictor of future cardiac events than perfusion abnormality in patients with IDCM.
Asunto(s)
Cardiomiopatía Dilatada/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Aumento de la Imagen/métodos , Isquemia Miocárdica/diagnóstico por imagen , Tomografía Computarizada de Emisión/métodos , Disfunción Ventricular Izquierda/diagnóstico por imagen , Factores de Edad , Cardiomiopatía Dilatada/complicaciones , Cardiomiopatía Dilatada/diagnóstico , Diagnóstico Diferencial , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/diagnóstico , Pronóstico , Protectores contra Radiación , Reproducibilidad de los Resultados , Medición de Riesgo/métodos , Sensibilidad y Especificidad , Factores Sexuales , Tomografía Computarizada de Emisión de Fotón Único/métodos , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/etiologíaRESUMEN
To examine the relationship between the plasma levels of angiogenic growth factors and the severity of cyanosis, 80 patients with cyanotic heart disease (CHD) and 81 healthy controls were studied. Median age and mean arterial blood oxygen saturation respectively were 4.2 years and 81% in CHD subjects and 4.8 years and 98% in controls. Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) were measured in plasma using enzyme-linked immunoassay. Plasma VEGF levels in controls depended negatively on age (p < 0.0001) until 3 months, when VEGF was no longer elevated. No such age dependence was found for HGF. Although VEGF levels did not differ between CHD and control subjects up to the age of 3 months, VEGF was significantly elevated in CHD patients older than 3 months compared to controls of similar age (149 +/- 106 vs 65 +/- 23 pg/ml, p < 0.0001). Moreover, the VEGF levels were negatively correlated with oxygen saturation (p = 0.03) and positively correlated with hemoglobin (p = 0.004) in CHD patients aged between 3 months and 10 years. Although the physiologic elevation of VEGF in the neonatal period decreases rapidly if oxygen saturation is normal, VEGF elevations persist if systemic hypoxia is present.
Asunto(s)
Factores de Crecimiento Endotelial/sangre , Cardiopatías Congénitas/diagnóstico , Factor de Crecimiento de Hepatocito/sangre , Péptidos y Proteínas de Señalización Intercelular/sangre , Linfocinas/sangre , Neovascularización Patológica/diagnóstico , Adolescente , Adulto , Análisis de Varianza , Biomarcadores/análisis , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Cianosis/complicaciones , Cianosis/diagnóstico , Femenino , Cardiopatías Congénitas/complicaciones , Humanos , Recién Nacido , Masculino , Probabilidad , Pronóstico , Medición de Riesgo , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
AIMS: Dispersion of ventricular depolarization-repolarization in 12-lead electrocardiograms (ECGs) has been reported to provide noninvasive information on arrhythmogenicity. However, there are two methods to calculate the dispersion from ECGs including and excluding limb leads. The aim of this study was to examine whether temporal parameters from limb leads represent activation and repolarization of a particular part of the body surface. METHODS AND RESULTS: We compared the temporal parameters of activation time (AT), activation-recovery interval (ARI), and recovery time (RT) from limb leads of ECGs with those from an 87-lead body surface maps. The study population consisted of 50 normal subjects (25 men and 25 women, 19.4 +/- 1.6 years). The temporal parameters in leads I, II, and III were highly (r > 0.9) correlated with those in unipolar leads over the left lateral, left lower, and right lower chest, respectively. The temporal parameters in leads aVR, aVL, and aVF showed a significant correlation (r > 0.8) with those in unipolar leads over the right upper, left upper, and lower anterior chest, respectively. The mean AT, ARI, and RT from each limb lead of ECG were almost the same as those of unipolar leads over the corresponding areas of the body surface. CONCLUSIONS: These findings suggest that ATs, ARIs, and RTs from limb leads may represent those from unipolar leads of particular areas over the body surface in normal subjects. The temporal parameters from limb leads of ECGs may provide information on activation and repolarization as well as the precordial leads of ECGs.