EFFECTS OF ENDOTHELINS ON COLLAGEN TURNOVER IN CARDIAC FIBROBLASTS

Objectives: Endothelins (ET-1 and ET-3) may be promoters of tissue remodelling, including fibrillar collagen accumulation. The hypothesis that ET-1 and ET-3 each modify cardiac fibroblast collagen turnover was tested. Methods: Confluent adult rat cardiac fibroblasts were maintained for 24 hours in medium with 0.4% fetal calf serum, and varying concentrations of ET-1 or ET-3. Collagen synthesis was measured by H-3-proline incorporation. The synthesis of type I and III collagens was measured by enzyme linked immunosorbent assay (ELISA). The effects of endothelins on collagenase activity were estimated by zymography. Results: ET-1 and ET-3 increased collagen synthesis in a concentration-dependent manner with a maximal 1.7-fold increase (p < 0.001 v control cells). The effects of ET-1 or ET-3 on collagen synthesis were not blocked by FED-3512-PI (10(-6) M), an ET(A) receptor antagonist. ET-1 and ET-3 each significantly (p < 0.01) increased the synthesis of both type I and III collagens. ET-1 caused a 5.8-fold decrease in collagenase activity (p < 0.01 v control), and this effect was blocked by FED-3512-PI (10(-6) M). ET-3 did not alter collagenase activity. Conclusion: ET-1 and ET-3 increased the synthesis of type I and In collagens, whereas ET-1, but not ET-3, reduced collagenase activity. The effects of endothelins on collagen synthesis in cardiac fibroblasts seem to be mediated through ET(A) and ET(B) receptors, whereas their effects on collagenase seem to be mediated by ET(A) receptors.