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J Biol Chem, Vol. 274, Issue 5, 3228-3234, January 29, 1999

Regulation of Endothelin-1 Synthesis by Endothelin-converting Enzyme-1 during Wound Healing

From the Duke University Liver Center and the Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710

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 on hepatic stellate cells, the key effectors 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 release from normal hepatic endothelial cells was 25-fold higher than that from normal stellate cells. However, after liver injury, ET-1 release was increased in stellate cells but markedly decreased in endothelial cells. The two major isoforms of ECE-1, ECE-1/1, made up 80% and 20%, respectively, of total ECE-1 in both stellate and endothelial cells. Following liver injury, ECE-1 mRNA was decreased by 44.2% in stellate cells, and by 16.1% in endothelial cells. ECE-1 mRNA expression remained unchanged after injury. In contrast to ECE-1 mRNA, ECE-1 protein expression was increased by 43.9% in stellate cells but decreased in endothelial cells, while relative ECE-1 enzymatic activity was unchanged. In mRNA stability experiments, the half-life of ECE-1 mRNA in normal stellate cells was 13 h compared with 38 h in cells from injured livers. Thus, during hepatic wound healing, differential regulation of ECE-1 mRNA and protein appears to be critical in controlling ET-1 production.

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