IMPAIRED GROWTH-RESPONSE TO ENDOTHELIN-1 IN SCLERODERMA FIBROBLASTS

Systemic sclerosis (SSc) is characterized by vascular damage and derma l fibrosis. In this study, we examined the endothelin (ET) receptor su btype involved in mitogenic signaling in scleroderma and normal skin f ibroblasts. ET-1 stimulated DNA synthesis of normal fibroblasts in ser um-deprived cultures. ET-3 had lesser effects on DNA synthesis of norm al fibroblasts than ET-1. The growth response to ET-1 in scleroderma f ibroblasts was decreased compared to normal fibroblasts. [I-125]-ET-1 binding to normal fibroblasts was significantly blocked by excessive a mount of unlabeled ET-1 and BQ-123. [I-125]-ET-1 binding to scleroderm a fibroblasts was significantly decreased compared with normal control s. Immunoblotting analysis showed that the expression of ETA receptor in scleroderma fibroblasts was diminished compared with normal control s. ETA mRNA expression in scleroderma fibroblasts was decreased compar ed with that of normal fibroblasts. From these results, we conclude th at the mitogenic effects of ET in human dermal fibroblasts are mainly mediated through ETA receptors, and that down-regulation of ETA recept ors caused the decreased growth response of ET-1 in scleroderma fibrob lasts. (C) 1995 Academic Press, Inc.