RESUMEN
Subunit 7a of mouse cytochrome c oxidase (Cox) displays a contractile muscle-specific isoform, Cox7a1, that is the major cardiac form. To gain insight into the role of this isoform, we have produced a new knockout mouse line that lacks Cox7a1. We show that homozygous and heterozygous Cox7a1 knockout mice, although viable, have reduced Cox activity and develop a dilated cardiomyopathy at 6 weeks of age. Surprisingly, the cardiomyopathy improves and stabilizes by 6 months of age. Cox7a1 knockout mice incorporate more of the "liver-type" isoform Cox7a2 into the cardiac Cox holoenzyme and, also surprisingly, have higher tissue ATP levels.
Asunto(s)
Cardiomiopatía Dilatada/genética , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Eliminación de Gen , Miocardio/patología , Animales , Masculino , Ratones , Ratones Noqueados , Subunidades de Proteína/genética , Análisis de SupervivenciaRESUMEN
Obesity-induced remodeling of cardiac extracellular matrix (ECM) leads to myocardial fibrosis and ultimately diastolic dysfunction. Leptin, an adipocyte hormone, is emerging as a novel mechanistic link between obesity and heart diseases. Despite the known essential role of leptin in hepatic and renal fibrosis, the in vivo effects of leptin on cardiac ECM remodeling remain unclear. Our objective was to define the role of leptin as a key mediator of pro-fibrogenic responses in the heart. In vitro administration of leptin to primary cardiofibroblasts resulted in significant stimulation of pro-collagen Iα ( 1 ) and a decrease in pro-matrix metalloproteinase (MMP)-8, -9 and -13 gene expressions at 24 h. To study the in vivo pro-fibrotic effect, leptin was administrated to C57BL/6 and leptin-deficient ob/ob mice for 8 weeks. With exogenous leptin ob/ob mice displayed passive diastolic filling dysfunction, coincided with significant increase in myocardial collagen compared with ob/ob controls. We also observed a marked stimulation of pro-collagen IIIα ( 1 ) and suppression of pro-MMP-8, TIMP-1 and -3 gene expressions in leptin-treated ob/ob mice. Our findings suggest pro-fibrotic effects of leptin in the heart, primarily through the predominance of collagen synthesis over degradation.