EFFECTS OF ENDOTHELINS ON COLLAGEN TURNOVER IN CARDIAC FIBROBLASTS

Objectives: Endothelins (ET-1 and ET-3) may be promoters of tissue rem odelling, including fibrillar collagen accumulation. The hypothesis th at ET-1 and ET-3 each modify cardiac fibroblast collagen turnover was tested. Methods: Confluent adult rat cardiac fibroblasts were maintain ed for 24 hours in medium with 0.4% fetal calf serum, and varying conc entrations of ET-1 or ET-3. Collagen synthesis was measured by H-3-pro line incorporation. The synthesis of type I and III collagens was meas ured by enzyme linked immunosorbent assay (ELISA). The effects of endo thelins on collagenase activity were estimated by zymography. Results: ET-1 and ET-3 increased collagen synthesis in a concentration-depende nt 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 b y 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 a nd III collagens. ET-1 caused a 5.8-fold decrease in collagenase activ ity (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 a nd ET-3 increased the synthesis of type I and In collagens, whereas ET -1, but not ET-3, reduced collagenase activity. The effects of endothe lins on collagen synthesis in cardiac fibroblasts seem to be mediated through ET(A) and ET(B) receptors, whereas their effects on collagenas e seem to be mediated by ET(A) receptors.