Effects of endothelins on hepatic stellate cell synthesis of endothelin-1 during hepatic wound healing.
Endothelin-1 production is increased after liver injury and the subsequent wounding response. Further, endothelin-1 has prominent effects on hepatic stellate cells (key effectors of the hepatic wounding response), including on collagen synthesis, proliferation, and expression of smooth muscle proteins. We tested the hypothesis that endothelins (ETs) may regulate endothelin-1 production during hepatic wounding, and have investigated potential mechanisms underlying this process. Studies were performed on isolated stellate cells from normal and injured livers; in addition, potential autocrine effects of ET were assessed in vivo using an ET receptor antagonist in a model of liver injury. In stellate cells isolated from either normal or injured rat livers, ET receptor stimulation with endothelin-3 or sarafotoxin S6C (preferential ET(B) agonists) caused a dose-dependent increase in endothelin-1 production. Additionally, administration of a mixed ET antagonist in vivo during injury led to reduced stellate cell production of endothelin-1. The mechanism by which ETs stimulated endothelin-1 in this system appeared to be through upregulation of ET converting enzyme-1 (which converts precursor ET to mature peptide), rather than by modulation of precursor endothelin-1. We conclude that during liver injury and wound healing, stellate cell endothelin-1 production is, at least partially, stimulated by ETs via autocrine mechanisms that occur at the level of ET converting enzyme-1.
Shao
Rong
R
Duke University Liver Center, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Rockey
Don C
DC
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D019898:Autocrine Communication / Q000502:physiology; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000494:pharmacology; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000502:physiology*; D008297:Male; D008666:Metalloendopeptidases; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology*
D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D012333:RNA, Messenger; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes