Mechanical load enhances the stimulatory effect of serum growth factors on cardiac fibroblast procollagen synthesis.

Abstract

The mechanical environment is a key determinant of cellular activity in many tissues. In the cardiovascular system it plays a role in tissue remodelling during both development and disease. In the heart changes in mechanical tension stimulate myocyte hypertrophy and fibroblast collagen synthesis. To elucidate the mechanisms for the latter response, we determined the direct effect of mechanical load on cardiac fibroblast activity. Primary cultures of fetal rat cardiac fibroblasts were mechanically loaded in the presence or absence of fetal calf serum or growth factors, and the effects on fibroblast replication and procollagen metabolism and gene expression determined. Procollagen synthesis was increased by 99.7 +/- 4.3% in response to mechanical load and 10% fetal calf serum, compared to 10% fetal calf serum control (P<0.01) after 48 h. Procollagen alpha1(I) steady-state mRNA levels were increased two-fold. No effect was observed in the absence of serum. Transforming growth factor beta1 and insulin-like growth factor 1 have been demonstrated to stimulate procollagen metabolism by these cells. Mechanical load enhanced the response to these growth factors, stimulating alpha1(I) mRNA levels by 4.3 and three-fold, respectively, above growth factor alone controls. These results demonstrate a synergistic effect on procollagen gene expression and metabolism by mechanical load and profibrotic growth factors. Since these factors are released during the development of cardiac hypertrophy, interactions between the mechanical environment and these polypeptides may provide a mechanism for enhanced collagen deposition in the heart.