Growth factor signal transduction in the cardiac myocyte: functions of the serum response element

Abstract

Historically, the question of whether cardiac muscle cells might be targets for the action of polypeptide growth factors was prompted, in equal measure, by analogy and incrimination: proof for the paramount role of growth factors in the skeletal muscle lineage as regulators of myogenesis [1, 2] and differentiation [3–7], and evidence that growth factor-like activity accumulates in myocardium after experimental aortic constriction, promoting amino acid incorporation into recipient cardiac tissue [8]. Despite more recent, specific clues as to the potential identity of myocardial growth factors [9]—isolation from myocardium or detection of several already-familiar peptide growth factors, [10–13], detailed mapping of growth factor expression within the heart by immunocytochemical methods and in situ hybridization [14–16], association of increased growth factor expression with certain mechanical or pharmacological models of hypertrophy [17–20]— there have been surprisingly few direct attempts to test the promising hypothesis that growth factors might modulate or govern critical aspects of the cardiac phenotype. One regrettable truism, which often is cited to help account for this paucity of information, alludes to the technical limitations commonly associated with, if not inherent to, primary cell culture, especially primary culture of ventricular myocytes. These experimental obstacles include dedifferentiation [21], heterogeneity of cell types [22], and logistical constraints arising from a relatively modest cell yield, compared to that achievable with immortalized cell lines or cells such as fibroblasts, with greater potential for proliferation in vitro. Ironically, several impediments have been in large part overcome through the use of culture media that contain non-mitogenic concentrations of serum or by the development of chemically defined media for cardiac cells that are free of exogenous growth factors [23]. Furthermore, the assumption that permanent cell lines necessarily model growth and gene expression with greater fidelity than newly dissociated cells has undergone increased scrutiny. For example, by comparison with skeletal muscle itself, many myogenic cell lines in widespread use express discrepant sets of myosin heavy chain isoforms [24], growth factor receptors [25], or muscle determination genes of the MyoD family [26, 27]. The two points of emphasis for the present review will be a survey of the growth factors that control a broad array of myocardial genes—notably, members of the heparin-binding, “fibroblast” growth factor (FGF) and type s transforming growth factor (TGFs) superfamilies—followed by a more intricate account of growth factor signal transduction in the case of a single gene, encoding the skeletal muscle isoform of α-actin, representative of a battery of genes associated jointly with early cardiac development and with myocardial hypertrophy. Other aspects of growth factor function in cardiac muscle cells such as contractile function and growth itself, along with additional information concerning the TGFs and FGF families, are detailed in contributions by Drs. Sporn and Kardami elsewhere in this volume.