Human heart failure: our current STATus of knowledge
Authors: V VANEMPEL, L DEWINDT
Journal: Cardiovascular Research (2003)

See article by Ng et al. [10] ( pages 333 -346) in thismented, noxious function of 'classical' ligands as neuroissue.hormones and the locally produced renin-angiotensin axis, pro-inflammatory cytokines are clearly locally hyperacti-Is this a dagger which I see before me . . .or art Thou vated during human heart failure [4][5][6][7].gp130 has been but a dagger of the mind . . .From Shakespeare's identified as a signal tranducing receptor for the Macbeth (II, I, 33).interleukin-6 (IL-6) family of cytokines [IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF) and cardiotrophin-1 1 .gp130 / STAT signaling and human heart failure (CT-1)] and displays a broad expression pattern, including the heart.Ligand binding to its cognate receptor induces Cardiac muscle hypertrophy involves the exuberant heterodimerization with gp130, leading to activation of growth of individual myofibers triggered by increased Janus kinase (JAK) and tyrosine phosphorylation of gp130 mechanical load (as in chronic hypertensive disease) or itself.This event in turn evokes the activation of a cascade decreased mechanical performance (as observed in is-of signal transduction pathways, involving STAT (signal chemic damage) and constitutes an independent clinical transducer and activator of transcription), Ras-MAPK risk factor for heart failure development [1,2].Conse-(mitogen activated protein kinase) and PI3K (phosphatidyl quently, elucidating the molecular circuitry controlling the inositol kinase) -Akt pathways, the activation of each initiation and maintenance of cardiac remodeling is the depends upon distinct regions of gp130 (Fig. 1) [8].focus of intense research in modern cardiovascular biolo-Studies from the immune biology field have provided gy.Integrative approaches have identified dozens of lig-evidence that JAKs and STATs play essential roles in ands, receptors, cytoplasmic signal amplifiers and tran-cytokine function [9].Three members of the JAK family, scriptional effectors of myocyte hypertrophy in the last JAK1, JAK2, and Tyk2, associate with and are activated decade [3].Nevertheless, the challenge remains to identify by the gp130 receptor following cytokine binding, which those common disease-provoking and -sustaining path-in their turn phosphorylate the latent, cytoplasmic tranways, given the variability in genetic susceptibility and scription factor STAT, allowing it to bind to its responsive environmental disparities of general human populations, to element in target genes (Fig. 1) [8].allow rational design of novel therapeutic targets, which An overwhelming body of cell culture and small animalmay eradicate the burden that heart failure places on the based studies indicates that cytokines operating through the health care system in industrialized countries.gp130 pathway are intimately involved in the development Cytokines are renowned as essential mediators of nor-of cardiac myocyte hypertrophy and apoptosis, two phemal and pathological immune responses.Whereas heart nomena closely associated with the development of human failure was conventionally viewed as an hemodynamic heart failure [4][5][6][7].Notwithstanding this evidence in disorder by clinicians, modern studies have revealed that experimental systems, any demonstration that the gp130 / excessive elaboration of organ-restricted ligands may play JAK / STAT signaling axis is activated in the diseased a much more intimate role in cardiac disease progression human heart would fortify these experimental conclusions.as previously suspected [1].In addition to the well-docu-The study of Ng et al. [10] in this issue of Cardiovascular Research for the first time demonstrates consistent tyrosine phosphorylation status of STAT1, 3, 5 and 6 in ventricular