RESUMO
Reduced expression of the key regulator of cardiac metabolism, transcription factor PPARα, in surgical samples of the auricles from patients with coronary heart disease and heart failure was detected by real-time quantitative PCR. These changes indicate reduced activity of this factor and a shift of energy metabolism from oxidative phosphorylation to glycolysis typical of dedifferentiated cells. Electron microscopy revealed dedifferentiated cardiomyocytes with disassembled contractile apparatus and disorganized sarcomeres. In the examined specimens from patients with heart failure, severe myocardial fibrosis was revealed.
Assuntos
Metabolismo Energético/fisiologia , Coração/fisiologia , Miócitos Cardíacos/metabolismo , PPAR alfa/fisiologia , Regeneração/fisiologia , Biópsia , Desdiferenciação Celular/genética , Doença das Coronárias/genética , Doença das Coronárias/metabolismo , Doença das Coronárias/patologia , Doença das Coronárias/fisiopatologia , Fibrose Endomiocárdica/genética , Fibrose Endomiocárdica/metabolismo , Fibrose Endomiocárdica/patologia , Fibrose Endomiocárdica/fisiopatologia , Metabolismo Energético/genética , Regulação da Expressão Gênica , Glicólise/genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Fosforilação Oxidativa , PPAR alfa/genética , PPAR alfa/metabolismoRESUMO
Pathological remodeling of the myocardium in chronic heart failure includes the development of pathological cardiac hypertrophy, reactivation of the fetal genetic program, and disorders in cardiac energy metabolism. Coactivator-1α of receptor γ activated by peroxisome proliferator (PGC-1α), a transcription coactivator of nuclear receptors and metabolism master regulator, plays an important role in cardiac metabolism regulation. Studies on the animals models of chronic heart failure have demonstrated the development of pathological cardiac hypertrophy, metabolic disorders, and reactivation of the fetal genetic program; these processes are mutually related. An important role in regulation of these processes belongs to PGC-1α; its low expression indicates low activity and down-regulation of this coactivator. Pathological cardiac hypertrophy, decrease of PGC-1α activity, and reactivation of the fetal genetic program in chronic heart failure are demonstrated.
Assuntos
Cardiomegalia/genética , Cardiomiopatia Dilatada/genética , Insuficiência Cardíaca/genética , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Adulto , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/fisiopatologia , Estudos de Casos e Controles , Feminino , Feto , Regulação da Expressão Gênica , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Miócitos Cardíacos/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Cultura Primária de CélulasRESUMO
We studied the localization of myosin-activating protein kinases in cardiomyocytes obtained from fetal human heart at 8-9 weeks gestation. It was found that at this developmental stage, smooth muscle/nonmuscle myosin light chain kinase (MLCK, 108 kDa) and its high-molecular weight isoform (MLCK, 210 kDa), skeletal MLCK and death-associated protein kinase (DAPK) are co-localized with nonmuscle myosin IIB in the premyofibrils. The data obtained suggest that cardiac nonmuscle myosin at 8-9 weeks gestation may serve as the substrate of the studied myosin-activating protein kinases that are likely to cooperatively regulate the formation of myofibrils. We revealed high-molecular weight isoform of smooth muscle/nonmuscle kinase MLCK-210 in developing human heart and determined the ratios of MLCK-108 and MLCK-210 at different gestational stages. In this case, the approximate time period of changes in these isoforms ratio was revealed (between 8-9 and 13 weeks), that can be associated with functional changes in the developing myocardium.
Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Coração/embriologia , Miócitos Cardíacos/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Miosinas/metabolismo , Células Cultivadas , Proteínas Quinases Associadas com Morte Celular , Feminino , Humanos , Miofibrilas/metabolismo , Gravidez , Sarcômeros/metabolismoRESUMO
It has been shown that Y-27632, an inhibitor of Rho-associated kinase, delays sarcomere assembly in rat neonatal cardiomyocytes pretreated with angiotensin II. Y-27632 affects the beat rate of cardiomyocytes; however, this effect is only observed at high cell density and, therefore, seems to be related to the formation of gap junctions between adjacent cardiomyocytes. Consistent with this suggestion, we established that Rho-associated kinase is localized in myofibrillar Z-discs of human myocardium and intercalated discs, the structures enriched in gap junctions. We propose that Rho-associated kinase participates in the maturation of the myocardial contractile system through phosphorylation of its molecular targets in Z-discs and intercalated discs.
