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Artigo em Inglês | MEDLINE | ID: mdl-30519544


Background: Archaeal genes present in Trypanosoma cruzi may represent symbionts that would explain development of heart failure in 30% of Chagas disease patients. Extracellular vesicles in peripheral blood, called exosomes (< 0.1 µm) or microvesicles (>0.1 µm), present in larger numbers in heart failure, were analyzed to determine whether they are derived from archaea in heart failure Chagas disease. Methods: Exosomes and microvesicles in serum supernatant from 3 groups were analyzed: heart failure Chagas disease (N = 26), asymptomatic indeterminate form (N = 21) and healthy non-chagasic control (N = 16). Samples were quantified with transmission electron microscopy, flow cytometer immunolabeled with anti-archaemetzincin-1 antibody (AMZ 1, archaea collagenase) and probe anti-archaeal DNA and zymography to determine AMZ1 (Archaeal metalloproteinase) activity. Results: Indeterminate form patients had higher median numbers of exosomes/case vs. heart failure patients (58.5 vs. 25.5, P < 0.001), higher exosome content of AMZ1 antigens (2.0 vs. 0.0; P < 0.001), and lower archaeal DNA content (0.2 vs. 1.5, P = 0.02). A positive correlation between exosomes and AMZ1 content was seen in indeterminate form (r = 0.5, P < 0.001), but not in heart failure patients (r = 0.002, P = 0.98). Higher free archaeal DNA (63.0 vs. 11.1, P < 0.001) in correlation with exosome numbers (r = 0.66, P = 0.01) was seen in heart failure but not in indeterminate form (r = 0.29, P = 0.10). Flow cytometer showed higher numbers of AMZ1 microvesicles in indeterminate form (64 vs. 36, P = 0.02) and higher archaeal DNA microvesicles in heart failure (8.1 vs. 0.9, P < 0.001). Zymography showed strong% collagenase activity in HF group, mild activity in IF compared to non-chagasic healthy group (121 ± 14, 106 ± 13 and 100; P < 0.001). Conclusions: Numerous exosomes, possibly removing and degrading abnormal AMZ1 collagenase, are associated with indeterminate form. Archaeal microvesicles and their exosomes, possibly associated with release of archaeal AMZ1 in heart failure, are future candidates of heart failure biomarkers if confirmed in larger series, and the therapeutic focus in the treatment of Chagas disease.

Archaea/fisiologia , Doença de Chagas/imunologia , Insuficiência Cardíaca/imunologia , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Bactérias/sangue , Biomarcadores , Doença de Chagas/sangue , Colagenases , Exossomos , Feminino , Citometria de Fluxo , Insuficiência Cardíaca/sangue , Humanos , Masculino , Metaloproteases , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade
Oncotarget ; 8(4): 6994-7002, 2017 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-28052002


Cardiotoxicity is associated with the chronic use of doxorubicin leading to cardiomyopathy and heart failure. Identification of cardiotoxicity-specific miRNA biomarkers could provide clinicians with a valuable prognostic tool. The aim of the study was to evaluate circulating levels of miRNAs in breast cancer patients receiving doxorubicin treatment and to correlate with cardiac function. This is an ancillary study from "Carvedilol Effect on Chemotherapy-induced Cardiotoxicity" (CECCY trial), which included 56 female patients (49.9±3.3 years of age) from the placebo arm. Enrolled patients were treated with doxorubicin followed by taxanes. cTnI, LVEF, and miRNAs were measured periodically. Circulating levels of miR-1, -133b, -146a, and -423-5p increased during the treatment whereas miR-208a and -208b were undetectable. cTnI increased from 6.6±0.3 to 46.7±5.5 pg/mL (p<0.001), while overall LVEF tended to decrease from 65.3±0.5 to 63.8±0.9 (p=0.053) over 12 months. Ten patients (17.9%) developed cardiotoxicity showing a decrease in LVEF from 67.2±1.0 to 58.8±2.7 (p=0.005). miR-1 was associated with changes in LVEF (r=-0.531, p<0.001). In a ROC curve analysis miR-1 showed an AUC greater than cTnI to discriminate between patients who did and did not develop cardiotoxicity (AUC = 0.851 and 0.544, p= 0.0016). Our data suggest that circulating miR-1 might be a potential new biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients.

Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/genética , Doxorrubicina/efeitos adversos , MicroRNAs/sangue , Biomarcadores , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Carbazóis , Cardiotoxicidade/sangue , Cardiotoxicidade/fisiopatologia , Carvedilol , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Propanolaminas , Curva ROC , Volume Sistólico/efeitos dos fármacos , Troponina C/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos
Nutrition ; 27(6): 713-8, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20934854


OBJECTIVE: Esterified cholesterol is the storage form of cholesterol in the organism. High-density lipoprotein (HDL), where free cholesterol is transferred from other lipoproteins and tissues, is the main esterification site in plasma. The aim of this study was to investigate how high cholesterol intake changes free/esterified ratios of cholesterol in the plasma, aorta, liver and lipid transfers to HDL. METHODS: Twenty male Golden Syrian hamsters fed 0.5% cholesterol for 15 wk and 19 controls without cholesterol feeding were sacrificed to determine serum lipids, transfer proteins (cholesteryl ester transfer protein and phospholipid transfer protein), and amount of free and esterified cholesterol in the aorta and liver. In vitro transfer of radioactive free and esterified cholesterol, phospholipids, and triacylglycerols to HDL was performed by incubating whole plasma with an artificial nanoemulsion used as a lipid donor and measuring radioactivity in the HDL fraction after chemical precipitation of non-HDL fractions and of the nanoemulsion. RESULTS: Compared with controls, cholesterol-fed animals showed a 137% increase in non-HDL plasma fraction and a 61% increase in HDL (P < 0.001). The esterified/free cholesterol ratio in non-HDL and HDL fractions did not change. In the aorta, free cholesterol increased 55% and the esterified/free ratio (0.2) decreased. Cholesterol accumulation in the liver was several-fold greater and esterified/free increased (1.3). Cholesterol feeding pronouncedly increased the transfer of free and esterified cholesterol, phospholipids, and triacylglycerols to HDL and cholesteryl ester transfer protein and phospholipid transfer protein activities. CONCLUSIONS: Free cholesterol is cytotoxic and less stable than esterified cholesterol, and the present data on how the organism responds to high cholesterol intake with respect to esterified/free ratios in the plasma, aorta, liver, and lipid transfers to HDL may have physiopathologic implications.

Aorta/metabolismo , Ésteres do Colesterol/metabolismo , Colesterol na Dieta/efeitos adversos , Colesterol/metabolismo , Lipoproteínas HDL/metabolismo , Fígado/metabolismo , Animais , Aorta/patologia , Aterosclerose/metabolismo , Transporte Biológico , Colesterol/sangue , Proteínas de Transferência de Ésteres de Colesterol/sangue , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Ésteres do Colesterol/sangue , Cricetinae , Dieta Aterogênica , Lipoproteínas HDL/sangue , Fígado/patologia , Masculino , Mesocricetus , Proteínas de Transferência de Fosfolipídeos/sangue , Proteínas de Transferência de Fosfolipídeos/metabolismo , Fosfolipídeos/sangue , Fosfolipídeos/metabolismo , Triglicerídeos/sangue , Triglicerídeos/metabolismo
J Physiol ; 588(Pt 13): 2431-42, 2010 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-20442263


Myocardial hypertrophy and dysfunction occur in response to excessive catecholaminergic drive. Adverse cardiac remodelling is associated with activation of proinflammatory cytokines in the myocardium. To test the hypothesis that exercise training can prevent myocardial dysfunction and production of proinflammatory cytokines induced by beta-adrenergic hyperactivity, male Wistar rats were assigned to one of the following four groups: sedentary non-treated (Con); sedentary isoprenaline treated (Iso); exercised non-treated (Ex); and exercised plus isoprenaline (Iso+Ex). Echocardiography, haemodynamic measurements and isolated papillary muscle were used for functional evaluations. Real-time RT-PCR and Western blot were used to quantify tumour necrosis factor alpha, interleukin-6, interleukin-10 and transforming growth factor beta(1) (TGF-beta(1)) in the tissue. NF-B expression in the nucleus was evaluated by immunohistochemical staining. The Iso rats showed a concentric hypertrophy of the left ventricle (LV). These animals exhibited marked increases in LV end-diastolic pressure and impaired myocardial performance in vitro, with a reduction in the developed tension and maximal rate of tension increase and decrease, as well as worsened recruitment of the Frank-Starling mechanism. Both gene and protein levels of tumour necrosis factor alpha and interleukin-6, as well as TGF-beta(1) mRNA, were increased. In addition, the NF-B expression in the Iso group was significantly raised. In the Iso+Ex group, the exercise training had the following effects: (1) it prevented LV hypertrophy; (ii) it improved myocardial contractility; (3) it avoided the increase of proinflammatory cytokines and improved interleukin-10 levels; and (4) it attenuated the increase of TGF-beta(1) mRNA. Thus, exercise training in a model of beta-adrenergic hyperactivity can avoid the adverse remodelling of the LV and inhibit inflammatory cytokines. Moreover, the cardioprotection is related to beneficial effects on myocardial performance.

Cardiomiopatias/prevenção & controle , Cardiomiopatias/fisiopatologia , Citocinas/metabolismo , Condicionamento Físico Animal/fisiologia , Receptores Adrenérgicos beta/fisiologia , Agonistas Adrenérgicos beta/farmacologia , Animais , Western Blotting , Cardiomegalia/induzido quimicamente , Cardiomegalia/fisiopatologia , Cardiomiopatias/induzido quimicamente , Cardiotônicos/farmacologia , Circulação Coronária/fisiologia , Ecocardiografia , Imuno-Histoquímica , Inflamação/metabolismo , Isoproterenol/farmacologia , Masculino , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , NF-kappa B/biossíntese , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/metabolismo , Função Ventricular Esquerda/fisiologia
Eur J Heart Fail ; 10(6): 534-9, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18502686


BACKGROUND: Sustained beta-adrenoreceptor activation promotes cardiac hypertrophy and cellular injury. AIMS: To evaluate the cardioprotective effect of exercise on damage induced by beta-adrenergic hyperactivity. METHODS: Male Wistar rats were randomised into four groups (n=8 per group): sedentary non-treated control (C), sedentary treated with isoproterenol 0.3 mg/kg/day administered subcutaneously for 8 days (I), exercised non-treated (E) and exercised plus isoproterenol administered during the last eight days of exercise (IE). Exercised animals ran on a treadmill for 1 h daily 6 times a week for 13 weeks. RESULTS: Isoproterenol caused increases in left ventricle (LV) wet and dry weight/body weight ratio, LV water content and cardiomyocyte transverse diameter. Additionally, isoproterenol induced severe cellular lesions, necrosis, and apoptosis, increased collagen content and reduced capillary and fibre fractional areas. Notably, all of these abnormalities were completely prevented by exercise. CONCLUSION: Our data have demonstrated that complete cardioprotection is possible through exercise training; by preventing beta-adrenergic hyperactivity-induced cardiac hypertrophy and structural injury.

Agonistas Adrenérgicos beta/efeitos adversos , Cardiomegalia/patologia , Cardiomegalia/prevenção & controle , Isoproterenol/efeitos adversos , Condicionamento Físico Animal , Receptores Adrenérgicos beta/fisiologia , Animais , Cardiomegalia/etiologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Marcação In Situ das Extremidades Cortadas , Masculino , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/efeitos dos fármacos