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1.
Oncotarget ; 8(4): 6994-7002, 2017 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-28052002

RESUMO

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.


Assuntos
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
2.
J Mol Cell Cardiol ; 51(5): 812-20, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21840315

RESUMO

We have recently shown that a temporary increase in sarcoplasmic reticulum (SR) cycling via adenovirus-mediated overexpression of sarcoplasmic reticulum ATPase (SERCA2) transiently improves relaxation and delays hypertrophic remodeling in a familial hypertrophic cardiomyopathy (FHC) caused by a mutation in the thin filament protein, tropomyosin (i.e., α-TmE180G or Tm180). In this study, we sought to permanently alter calcium fluxes via phospholamban (PLN) gene deletion in Tm180 mice in order to sustain long-term improvements in cardiac function and adverse cardiac remodeling/hypertrophy. While similar work has been done in FHCs resulting from mutations in thick myofilament proteins, no one has studied these effects in an FHC resulting from a thin filament protein mutation. Tm180 transgenic (TG) mice were crossbred with PLN knockout (KO) mice and four groups were studied in parallel: 1) non-TG (NTG), 2) Tm180, 3) PLNKO/NTG and 4) PLNKO/Tm180. Tm180 mice exhibit increased heart weight/body weight and hypertrophic gene markers compared to NTG mice, but levels in PLNKO/Tm180 mice were similar to NTG. Tm180 mice also displayed altered function as assessed via in situ pressure-volume analysis and echocardiography at 3-6 months and one year; however, altered function in Tm180 mice was rescued back to NTG levels in PLNKO/Tm180 mice. Collagen deposition, as assessed by Picrosirius Red staining, was increased in Tm180 mice but was similar in NTG and in PLNKO/Tm180 mice. Extracellular signal-regulated kinase (ERK1/2) phosphorylation increased in Tm180 mice while levels in PLNKO/Tm180 mice were similar to NTGs. The present study shows that by modulating SR calcium cycling, we were able to rescue many of the deleterious aspects of FHC caused by a mutation in the thin filament protein, Tm.


Assuntos
Biomarcadores/metabolismo , Proteínas de Ligação ao Cálcio/deficiência , Cálcio/metabolismo , Cardiomiopatia Hipertrófica Familiar , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Tropomiosina/genética , Animais , Peso Corporal , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/uso terapêutico , Cardiomiopatia Hipertrófica Familiar/diagnóstico por imagem , Cardiomiopatia Hipertrófica Familiar/genética , Cardiomiopatia Hipertrófica Familiar/metabolismo , Cardiomiopatia Hipertrófica Familiar/fisiopatologia , Cardiomiopatia Hipertrófica Familiar/terapia , Modelos Animais de Doenças , Ecocardiografia , MAP Quinases Reguladas por Sinal Extracelular/genética , Expressão Gênica , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Contração Miocárdica/genética , Miocárdio/citologia , Miocárdio/metabolismo , Tamanho do Órgão , Fosforilação , Reação em Cadeia da Polimerase em Tempo Real , Retículo Sarcoplasmático/genética , Retículo Sarcoplasmático/metabolismo , Tropomiosina/metabolismo
3.
Am J Physiol Heart Circ Physiol ; 301(4): H1646-55, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21743000

RESUMO

The effects of nicotine (NIC) on normal hearts are fairly well established, yet its effects on hearts displaying familial hypertrophic cardiomyopathy have not been tested. We studied both the acute and chronic effects of NIC on a transgenic (TG) mouse model of FHC caused by a mutation in α-tropomyosin (Tm; i.e., α-Tm D175N TG, or Tm175). For acute effects, intravenously injected NIC increased heart rate, left ventricular (LV) pressure, and the maximal rate of LV pressure increase (+dP/dt) in non-TG (NTG) and Tm175 mice; however, Tm175 showed a significantly smaller increase in the maximal rate of LV pressure decrease (-dP/dt) compared with NTGs. Western blots revealed phosphorylation of phospholamban Ser16 and Thr17 residue increased in NTG mice following NIC injection but not in Tm175 mice. In contrast, phosphorylation of troponin I at serine residues 23 and 24 increased equally in both NTG and Tm175. Thus the attenuated increase in relaxation in Tm175 mice following acute NIC appears to result primarily from attenuated phospholamban phosphorylation. Chronic NIC administration (equivalent to smoking 2 packs of cigarettes/day for 4 mo) also increased +dP/dt in NTG and Tm175 mice compared with chronic saline. However, chronic NIC had little effect on heart rate, LV pressure, -dP/dt, LV wall and chamber dimensions, or collagen content for either group of mice.


Assuntos
Cardiomiopatia Hipertrófica Familiar/tratamento farmacológico , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Tropomiosina/genética , Animais , Pressão Sanguínea/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Cardiomiopatia Hipertrófica Familiar/genética , Cardiomiopatia Hipertrófica Familiar/fisiopatologia , Separação Celular , Colágeno/metabolismo , Ecocardiografia , Feminino , Corantes Fluorescentes , Fura-2 , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Masculino , Camundongos , Contração Miocárdica/efeitos dos fármacos , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular/efeitos dos fármacos
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