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Signalling and regulation of collagen I synthesis by ET‐1 and TGF‐β1
Author(s) -
Horstmeyer Angelika,
Licht Christoph,
Scherr Gabriele,
Eckes Beate,
Krieg Thomas
Publication year - 2005
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2005.05016.x
Subject(s) - ctgf , phospholipase c , transforming growth factor , receptor , phospholipase d , phospholipase , protein kinase c , medicine , endocrinology , microbiology and biotechnology , chemistry , growth factor , signal transduction , biology , biochemistry , enzyme
Endothelin‐1 (ET‐1) plays an important role in tissue remodelling and fibrogenesis by inducing synthesis of collagen I via protein kinase C (PKC). ET‐1 signals are transduced by two receptor subtypes, the ETA‐ and ETB‐receptors which activate different Gα proteins. Here, we investigated the expression of both ET‐receptor subtypes in human primary dermal fibroblasts and demonstrated that the ETA‐receptor is the major ET‐receptor subtype expressed. To determine further signalling intermediates, we inhibited Gαi and three phospholipases. Pharmacologic inhibition of Gαi, phosphatidylcholine‐phospholipase C (PC‐PLC) and phospholipase D (PLD), but not of phospholipase Cβ, abolished the increase in collagen I by ET‐1. Inhibition of all phospholipases revealed similar effects on TGF‐β1 induced collagen I synthesis, demonstrating involvement of PC‐PLC and PLD in the signalling pathways elicited by ET‐1 and TGF‐β1. ET‐1 and TGF‐β1 each stimulated collagen I production and in an additive manner. ET‐1 further induced connective tissue growth factor (CTGF), as did TGF‐β1, however, to lower levels. While rapid and sustained CTGF induction was seen following TGF‐β1 treatment, ET‐1 increased CTGF in a biphasic manner with lower induction at 3 h and a delayed and higher induction after 5 days of permanent ET‐1 treatment. Coincidentally at 5 days of permanent ET‐1 stimulation, a switch in ET‐receptor subtype expression to the ETB‐receptor was observed. We conclude that the signalling pathways induced by ET‐1 and TGF‐β1 leading to augmented collagen I production by fibroblasts converge on a similar signalling pathway. Thereby, long‐time stimulation by ET‐1 resulted in a changed ET‐receptor subtype ratio and in a biphasic CTGF induction.