Effects of transforming growth factor-beta on cardiac fibroblasts

Abstract

Cardiac cells consist of cardiac myocytes and non-myocyte cells. The non-myocyte population includes cardiac fibroblasts that are present in the interstitium, endothelial cells that form the lining of blood vessels and myocardial cavities, smooth muscle cells, and nerve cells. By the use of monospecific antibodies to each cell type and immunofluorescent staining of freshly isolated non-myocyte heart cells, we have established that greater than 90% of the heart cells in the non-myocyte population are cardiac fibroblasts [1]. In the ventricular myocardium, cardiac fibroblasts are responsible for biosynthesis of extracellular matrix proteins [1,2]. In the heart, extracellular matrix provides structural and functional support for cardiac myocytes and the vasculature. Major protein of this matrix is collagen. Collagens are a family of related molecules with distinct genes and variable tissue distribution. Major collagens of the adult heart are classical fiber-forming collagen types I and III, and basement membrane-specific collagen type IV. Collagen type I accounts for greater than 80% of total collagens in the heart [3]. A normal collagen matrix that is the result of a balanced collagen synthesis and degradation process is critical for maintaining the integrity of myocardial function. In the interstitium, cardiac fibroblasts are exposed to the regulatory effects of various hormones, neurotransmitters and growth factors that are present in the myocardium or gain access to the ventricular tissue by blood vessels. Regulation of gene expression in cardiac fibroblasts and modulation of their phenotype by those regulatory factors may occur under various pathophysiological conditions. Transforming growth factor-beta (TGF-ß₁) is a multi-functional growth factor peptide that is present in the myocardium in areas surrounding the blood vessels [4]. It has been shown that TGF-ß₁ regulates biosynthesis of collagen type I both at transcriptional and post-transcriptional levels [5]. In this chapter, I review the results of our studies that indicate cardiac fibroblasts are cellular targets for the regulatory effects of TGF-ß₁ in the heart and that the interstitial compartment of the heart may be altered both structurally and functionally as the result of the effects of TGF-ß₁, both on collagen gene expression and on cardiac fibroblast phenotype.