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 (it is a review paper). 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.

Insulin-like growth factor I (IGF-1) is a single-chain polypeptide that has insulin-like short term metabolic effects and growth factor-like long term effects on cell proliferation and differentiation. The binding of IGF-1 to its cell surface receptor (IGF-1R) activates the receptor's intrinsic tyrosine kinase activities, which results in the phosphorylation of the insulin receptor substrates (IRS-1 and IRS-2). Tyrosine-phosphorylated IRSs interact with cytoplasmic proteins with src homology 2 (SH2) domains, such as phosphatidylinositol 3-kinase (PI3K). PI3K activation then leads to the transduction of the functional effects of IGF-1, such as enhanced glucose transport, enhanced cardiomyocyte contractility, and the inhibition of programmed cell death (apoptosis).

Alterative signalling pathways triggered by IGF-1-receptor binding begin with the association of growth receptor binding protein 2 (GRB2) with Son of sevenless (SOS) and phosphorylated Shc. This then activates Ras and initiates sequential phosphorylation cascades involving serine/threonine kinase (Raf), MAP kinase kinase kinase (MEKK), MAP kinase kinase (MEK), extracellular signal-regulated kinase (ERK) and c-Jun NH₂ terminal kinase (JNK) (see the figure below).

IGF-1 signalling plays numerous roles in both physiological and pathophysiological conditions. Under normal physiological conditions IGF-1 enhances DNA and protein synthesis in cardiomyocytes, it promotes myofibril development, and it is necessary for entry into the S-phase of the cell cycle. IGF-1 also has an important role in the development of the hypertrophic response, where it enhances the expression of contractile proteins such as actin, myosin and troponin. Through its tyrosine kinase, PI3 kinase and MAP kinase signalling pathways, IGF-1 may also reduce the risk of heart failure through the prevention of apoptosis.

In their 1999 paper, Ren, Samson and Sowers look at the roles of IGF-1 in heart disease (the complete original paper reference is cited below). They found that IGF-1 plays a specific role in the complex cascade of events of cardiovascular growth and function, and that it also plays a role in the development of cardiac hypertrophy.

Insulin-like Growth Factor I as a Cardiac Hormone: Physiological and Pathophysiological Implications in Heart Disease, Jun Ren, Willis K. Samson, and James R. Sowers, 1999, Journal of Molecular and Cellular Cardiology , 31, 2049-2061. (A PDF version of the article is available to subscribers on the Journal of Molecular and Cellular Cardiology website.)

Signal Transduction Pathway Diagram

Schematic diagram of the signal transduction cascades that are involved in IGF-1-mediated cardiac hypertrophy.

• ren_samson_sowers_1999_version01.cellml