RESUMO
PURPOSE: Cardiotoxicity is a well-known side effect of chloroquine. Several studies have proposed chloroquine as a potential anti-diabetic treatment but do not address this problem. The current study investigated the effect of ex vivo chloroquine treatment on (1) heart function and glucose uptake, (2) mitochondrial function and (3) in vivo treatment on heart function. METHODS: Control or obese male Wistar rats were used throughout. Dose responses of increasing chloroquine concentrations versus vehicle on cardiac function were measured using isolated, Langendorff-perfused hearts whilst glucose uptake and cell viability were determined in ventricular cardiomyocytes. Mitochondrial function was assessed with a Clark-type oxygraph (Hansatech) after ex vivo perfusion with 30 µM chloroquine versus vehicle. Animals were treated orally with 5 mg/kg/day chloroquine for 6 weeks. RESULTS: Acute chloroquine treatment of 10 µM was sufficient to significantly decrease heart function (p < 0.05) whilst 30 µM significantly reduced heart rate (p < 0.05). Chloroquine became toxic to isolated cardiomyocytes at high concentrations (100 µM), and had no effect on cardiomyocyte glucose uptake. Ex vivo treatment did not affect mitochondrial function, but chronic low-dose in vivo chloroquine treatment significantly decreased aortic output and total work in hearts (p < 0.005). CONCLUSION: Low and intermediate chloroquine doses administered either chronically or acutely are sufficient to result in myocardial dysfunction.
Assuntos
Antimaláricos/toxicidade , Cloroquina/toxicidade , Cardiopatias/induzido quimicamente , Mitocôndrias Cardíacas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Animais , Cardiotoxicidade , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Metabolismo Energético/efeitos dos fármacos , Glucose/metabolismo , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Preparação de Coração Isolado , Masculino , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Obesidade/metabolismo , Obesidade/patologia , Obesidade/fisiopatologia , Ratos Wistar , Medição de Risco , Fatores de TempoRESUMO
The ataxia-telangiectasia mutated (ATM) protein kinase is well known to play a significant role in the response to double stranded DNA breaks in the nucleus. Recently, it has become apparent that ATM is also involved in a large number of cytoplasmic processes and responses, some of which may contribute to metabolic and cardiovascular complications when disrupted. Due to its involvement in these processes, therapeutic activation of ATM could potentially be a novel approach for the prevention or treatment of cardiovascular disease. However, relatively little is currently known about the cardiovascular role of ATM. In this review, we highlight studies that have shed some light on the role of ATM in the cardiovascular context, namely in oxidative stress, atherosclerosis and metabolism, insulin resistance and cardiac remodeling.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Animais , Humanos , Resistência à Insulina , Estresse Oxidativo , Transdução de SinaisRESUMO
Endornaviruses have large double-stranded RNA (dsRNA) genomes that carry a single open reading frame (ORF). Here we report the complete genome of a novel endornavirus, assembled from next-generation sequence data generated from Vitis vinifera-extracted dsRNA. Two different fungal hosts have been identified for this virus, suggesting that horizontal transmission of the virus is possible.
