gp130-Mediated Pathway and Heart Failure

Binding of ligands to gp130 activates at least three different downstream signaling pathways: the signal transducer and activator of transcription (STAT), the Src-homology tyrosine phosphatase 2-ras-MAPK and the PI3K/Akt pathways. Cardiac-specific disruption of gp130 was shown to result in heart failure in response to mechano-stress accompanied by an increase in apoptosis of cardiac myocytes. Inactivation of STAT3 resulting from the loss of gp130 may be a key event in the transition from cardiac hypertrophy to heart failure. Proper vascular growth would be essential for normal cardiac development and the remodeling process. In addition to various factors, such as bcl-xL, inducible nitric oxide synthase and reactive oxygen species-scavenging proteins, VEGF has also been identified as a target gene of STAT3 and together can promote cardiac myocyte survival by preventing apoptosis and restoration of energy deprivation. In this regard, the gp130-receptor system and its main downstream mediator, STAT3, play a key role in the prevention of heart failure. In this review, current knowledge of the IL-6 family of cytokines relating to human cardiac disease is summarized, in addition to the potential role of gp130-mediated signaling systems in various models of experimental heart failure.