Impaired growth response to endothelin-1 in scleroderma fibroblasts.
Systemic sclerosis (SSc) is characterized by vascular damage and dermal fibrosis. In this study, we examined the endothelin (ET) receptor subtype involved in mitogenic signaling in scleroderma and normal skin fibroblasts. ET-1 stimulated DNA synthesis of normal fibroblasts in serum-deprived cultures. ET-3 had lesser effects on DNA synthesis of normal fibroblasts than ET-1. The growth response to ET-1 in scleroderma fibroblasts was decreased compared to normal fibroblasts. [125I]-ET-1 binding to normal fibroblasts was significantly blocked by excessive amount of unlabeled ET-1 and BQ-123. [125I]-ET-1 binding to scleroderma fibroblasts was significantly decreased compared with normal controls. Immunoblotting analysis showed that the expression of ETA receptor in scleroderma fibroblasts was diminished compared with normal controls. ETA mRNA expression in scleroderma fibroblasts was decreased compared with that of normal fibroblasts. From these results, we conclude that the mitogenic effects of ET in human dermal fibroblasts are mainly mediated through ETA receptors, and that down-regulation of ETA receptors caused the decreased growth response of ET-1 in scleroderma fibroblasts.
Kikuchi
K
K
Department of Dermatology, University of Tokyo Branch Hospital, Japan.
Kadono
T
T
Sato
S
S
Tamaki
K
K
Takehara
K
K
D001706:Biopsy; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D007700:Kinetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D017466:Receptors, Endothelin / Q000096:biosynthesis / Q000302:isolation & purification / Q000502:physiology*; D012016:Reference Values; D012595:Scleroderma, Systemic / Q000473:pathology*; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D013936:Thymidine / Q000378:metabolism; D014471:Umbilical Veins
D016232:Endothelins; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D013936:Thymidine