Model Status

This CellML model still contains the reaction element. We have been unable to recode this model to remove the reaction element because the published paper does not contain a quantitative model. Therefore this CellML model is a purely qualitative model it and contains no mathematical description of the pathways defined. All the rates and concentrations have been set to 1.0.

Signal Transduction Pathway

Cardiac hypertrophy describes an abnormal condition where the heart becomes enlarged. Under stresses such as high blood pressure, or reduced blood flow through the coronary arteries, the heart must work harder. Instead of dividing and increasing in number, individual cells grow larger and genes normally expressed in the embryonic ventricle are reexpressed. Initially this compensation is effective, but excessive hypertrophy can kill more cells, which increases the stress on the heart, causing surviving cells to grow even larger, which in turn leads to an ever accelerating cycle that can eventually result in heart failure. Cardiac hypertrophy can also cause diseases such as myocardial infarction and arrhythmia, and therefore it is important to try and better understand the molecular mechanisms underlying the development of this condition.

The interleukin-6 (IL-6) family of cytokines (IL-6, IL-11, oncostatin M, ciliary neurotrophic factor, cardiotrophin- 1 and leukemia inhibitory factor (LIF)) plays an important role in cardiac myocyte maturation and in the development of cardiac hypertrophy. The binding of LIF to its receptor activates Janus kinases (JAKs) which then phosphorylate gp130, producing binding sites for proteins with src homology 2 (SH2) domains, such as growth factor receptor bound protein 2 (GRB2). This is then the starting point for a Ras/Raf/MEK/ERK/p90RSK cascade (for more details see a description of a Ras signalling cascade [Ras_cascade_doc.html]). The family of signal transducer and activator of transcription (STAT) are also SH2 domain containing factors that are able to bind to the phosphorylated gp130. They subsequently become phosphorylated and translocated into the nucleus. A third alternative signalling pathway triggered by gp130 activation is the phosphorylation and activation of phosphatidylinositide 3-kinase (PI3K). PI3K activates Akt kinase and plays an important role in protein synthesis via p70 S6 kinase (p70S6K) (see the figure below).

In their 2000 paper, Kodama et al. compare the significance of these three signal transduction cascades in the development of gp130-mediated cardiac hypertrophy. (The complete original paper reference is cited below). They found that all three pathways resulted in increased protein synthesis and an increase in cell size, and both these features are positively correlated with cardiac hypertrophy. The three pathways differentially activated hypertrophic marker gene expression. To different degrees all three pathways enhanced the expression of c-fos, brain natriuretic peptide (BNP), skeletal alpha-actin, and atrial natriuretic peptide (ANP). They found that c-fos, BNP and skeletal alpha-actin genes are induced most significantly by the ERK cascade. ANP expression is most dependent on the JAK/STAT pathway, as is myofilament reorganisation.

Significance of ERK cascade compared with JAK/STAT and PI3-K pathway in gp130-mediated cardiac hypertrophy, Kodama H, Fukuda K, Pan J, Sano M, Takahashi T, Kato T, Makino S, Manabe T, Murata M, Ogawa S, 2000 American Journal of Physiology - Heart and Circulatory Physiology , 279, H1635-H1644. (Full text and PDF versions of the article are available to subscribers on the American Journal of Physiology website.)

Signal Transduction Pathway Diagram

Schematic diagram of the signal transduction cascades that are involved in gp130-mediated cardiac hypertrophy.

• kodama_fukuda_pan_sano_takahashi_kato_makino_manabe_murata_ogawa_2000_version01.cellml