SIGNALING PATHWAYS IN CARDIAC MYOCYTE HYPERTROPHY

When a heart responds to increased workload it does so by hypertrophy, This is characterized by an increase in cell size in the absence of c ell division, and is accompanied by distinct qualitative and quantitat ive changes in gene expression. The use of cardiomyocytes in cell cult ure has identified, besides mechanical loading, a range of substances, such as cytokines, growth factors, catecholamines, vasoactive peptide s and hormones, involved in mediating cardiac myocyte hypertrophy, and has enabled the molecular dissection of the pathways involved in sign al transduction. Many different pathways are activated in response to different hypertrophic stimuli, and a growing number of crosslinks are being characterized between these pathways. Recent evidence suggests a central role for Ras in transmitting signals from G-protein coupled receptors, from growth factor receptors and from cytokine receptors no t only down the Raf-MEK-ERK pathway to the nucleus, but also to variou s other cytosolic effecters. The evaluation of distinct morphological phenotypes, together with biochemical data on gene regulation, suggest s that interactions between different signaling pathways take place. E ach stimulus provokes a typical cellular phenotype and different stimu li may act alone or in concert in a synergistic, antagonistic or permi ssive manner. Consequently, hypertrophy of cultured cardiomyocytes can not simply be characterized as the reversal to the fetal gene expressi on program. Thus, hypertrophic growth of the heart may similarly be th e result of a complex combinatorial action of various stimuli, which m ay also lead to different morphological and biochemical phenotypes wit h distinct physiological properties. (C) 1997 Academic Press Limited.