TAILIEUCHUNG - Báo cáo khoa học: Signalling and regulation of collagen I synthesis by ET-1 and TGF-b1

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 Gaproteins. | ềFEBS Journal Signalling and regulation of collagen I synthesis by ET-1 and TGF-p1 Angelika Horstmeyer1 Christoph Licht2 Gabriele Scherr1 Beate Eckes1 and Thomas Krieg1 1 Department of Dermatology and 2 Children s Hospital University of Cologne Cologne Germany Keywords Connective tissue growth factor dermal fibroblast endothelin receptor subtypes fibrosis phospholipase Correspondence A. Horstmeyer Department of Dermatology University of Cologne Joseph-Stelzmann-Str. 9 D-50931 Cologne Germany Fax 49 221 478 5949 Tel 49 221 478 6152 E-mail ahorstmey@ Received 29 May 2005 revised 7 October 2005 accepted 13 October 2005 doi 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 Ga 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 Gai and three phospholipases. Pharmacologic inhibition of Gai phosphatidylcholine-phospholipase C PC-PLC and phospholipase D PLD but not of phospholipase Cb abolished the increase in collagen I by ET-1. Inhibition of all phospholipases revealed similar effects on TGF-p1 induced collagen I synthesis demonstrating involvement of PC-PLC and PLD in the signalling pathways elicited by ET-1 and TGF-p1. ET-1 and TGF-p1 each stimulated collagen I production and in an additive manner. ET-1 further induced connective tissue growth factor CTGF as did TGF-p1. however to lower levels. While rapid and sustained CTGF induction was seen following TGF-p1 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

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