Cardiotrophin-1 in heart failure.

Abstract

Cardiotrophin-1 (CT-1) is a 201 amino acid1 member of the interleukin (IL)-6 cytokine superfamily, which includes leukemia inhibitory factor (LIF), ciliary neurotrophic factor, IL-11, and oncostatin M.2 Cardiotrophin-1 was discovered by Pennica et al2 via expression cloning of mouse embryoid bodies, using a cardiac myocyte hypertrophy screen to identify positive clones. CT-1 has hypertrophic and cardioprotective properties and acts through LIF receptor β/glycoprotein 130 (gp130)-coupled signaling pathways. The LIF receptor binds CT-1, and then gp130 associates with the ligand-receptor complex and transduces the proximal signal. CT-1 intracellular signaling pathways include extracellular signal regulated kinases (ERK), mitogen activated protein (MAP) kinases, the janus kinase (JAK)/signal transducers and activators of transcription (STAT) system, and PI3-kinase/Akt. Downstream mediators of CT-1’s cellular effects include multiple ERK-coupled transcription factors, STAT-3, nuclear factor-κB, and heat shock proteins 56, 70, and 90. Cardiac CT-1 expression is increased by hypoxia, where it protects cardiac myocytes from ischemic and reperfusion injury and apoptosis. See p 1442 As described shortly after its discovery, CT-1 promotes cardiac myocyte hypertrophy by directing sarcomere assembly in series.3 At the ventricular structural level, in-series sarcomeric assembly leads to “eccentric” hypertrophy and chamber dilatation. Thus, increased myocardial expression of CT-1 immediately became a candidate for the molecular basis of pathological hypertrophy and remodeling in dilated cardiomyopathy phenotypes. The cardiac myocyte protective effects were also appreciated early in the investigation of CT-1’s biological properties.4 Mice with genetic ablation of gp130 have hypoplastic hearts,5 which suggests a role for CT-1 or other IL-6–type cytokines in normal cardiac development. However, mice with ventricular myocyte-restricted knockout of gp130 using a ventricular myosin light chain 2 promoter that drives a Cre/lox recombination/knockout system from early in development have no cardiac abnormalities at birth,6 indicating that the …