Regulation of endothelin-1 synthesis by endothelin-converting enzyme-1 during wound healing

Endothelin-1 (ET-1) is involved in the pathogenesis of a number of diseases , including wound healing. In cirrhosis, the wounding response of the liver , circulating ET-1 levels are elevated; moreover, ET-1 has potent effects o n hepatic stellate cells, the key effecters of cirrhosis. In this study, we have examined the regulatory role of ECE-1, a critical enzyme involved in ET-1 synthesis, in the two major cellular sources of hepatic ET-1, ET-1 rel ease from normal hepatic endothelial cells was 25-fold higher than that fro m normal stellate cells. However, after liver injury, ET-1 release was incr eased in stellate cells but markedly decreased in endothelial cells. The tw o major isoforms of ECE-1, ECE-1 alpha/1 beta, made up 80% and 20%, respect ively, of total ECE-1 in both stellate and endothelial cells. Following liv er injury, ECE-1 alpha mRNA was decreased by 44.2% in stellate cells, and b y 16.1% in endothelial cells. ECE-1 beta mRNA expression remained unchanged after injury. In contrast to ECE-1 mRNA, ECE-1 protein expression was incr eased by 43.9% in stellate cells but decreased in endothelial cells, while relative ECE-1 enzymatic activity was unchanged. In mRNA stability experime nts, the half-life of ECE-alpha mRNA in normal stellate cells was 13 h comp ared with 38 h in cells from injured livers. Thus, during hepatic wound hea ling, differential regulation of ECE-1 mRNA and protein appears to be criti cal in controlling ET-1 production.