A GROWTH-FACTOR FOR CARDIAC MYOCYTES IS PRODUCED BY CARDIAC NONMYOCYTES

Cardiac nonmyocytes, primarily fibroblasts, surround cardiac myocytes in vivo. We examined whether nonmyocytes could modulate myocyte growth by production of one or more growth factors. Cardiac myocyte hypertrophic growth was stimulated in cultures with increasing numbers of cardiac nonmyocytes. This effect of nonmyocytes on myocyte size was reproduced by serum-free medium conditioned by the cardiac nonmyocytes. The majority of the nonmyocyte-derived myocyte growth-promoting activity bound to heparin-Sepharose and was eluted with 0.75 M NaCl. Several known polypeptide growth factors found recently in cardiac tissue, namely acidic fibroblast growth factor (aFGF), basic FGF (bFGF), platelet-derived growth factor (PDGF), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta-1 (TGF-beta-1), also caused hypertrophy of cardiac myocytes in a dose-dependent manner. However, the nonmyocyte-derived growth factor (tentatively named NMDGF) could be distinguished from these other growth factors by different heparin-Sepharose binding profiles (TNF-alpha, aFGF, bFGF, and TGF-beta-1) by neutralizing growth factor-specific antisera (PDGF, TNF-alpha, aFGF, bFGF, and TGF-beta-1), by the failure of NMDGF to stimulate phosphatidylinositol hydrolysis (PDGF and TGF-beta-1), and, finally, by the apparent molecular weight of NMDGF (45-50 kDa). This nonmyocyte-derived heparin-binding growth factor may represent a novel paracrine growth mechanism in myocardium.