Abstract
Accumulating evidence suggests that interleukin-1 (IL-1) signaling plays an essential role in the pathogenesis of heart failure by inducing cardiomyocyte apoptosis, but the mechanisms of this process are poorly defined. We further explored these molecular pathways. We isolated cardiomyocytes from neonatal mice and then cultured and stimulated them with murine IL-1β in vitro. Cell apoptotic ratios were measured by means of flow cytometry. Expression of effector molecules was analyzed by means of enzyme-linked immunosorbent assay, Western blotting, and real-time quantitative polymerase chain reaction. The results showed that IL-1β induced murine cardiomyocyte apoptosis through a release of cytochrome c into cytoplasm and through caspase 3 activation. Simultaneously, IL-1β signaling promoted expression of endonuclease G and high-temperature requirement protein A2 messenger RNA. Survivin and X-linked inhibitors of apoptosis protein (IAP), members of the IAP family, were inhibited on the messenger RNA level during IL-1β-mediated cardiomyocyte apoptosis. We found that IL-1β signaling during cardiomyocyte apoptosis in vitro induced the activation of caspase-dependent and caspase-independent pathways, and inhibited IAPs. Understanding the molecular mechanisms involved in IL-1β-mediated cardiomyocyte apoptosis might assist in the design of therapeutic approaches to protect cardiomyocyte function and prevent heart failure.
Keywords:
Apoptosis/physiology; apoptosis regulatory proteins; caspases/metabolism; cytokines/physiology; disease models/animal; heart diseases/immunology/metabolism; interleukin-1/antagonists & inhibitors; interleukin-1beta/immunology/metabolism/physiology; mice; myocytes, cardiac/metabolism; signal transduction.