Abstract
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-1alpha/1beta, made up 80% and 20%, respectively, of total ECE-1 in both stellate and endothelial cells. Following liver injury, ECE-1alpha mRNA was decreased by 44.2% in stellate cells, and by 16.1% in endothelial cells. ECE-1beta 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-1alpha 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.
Highlights
The family of endothelins is comprised of three 21-residue peptides, endothelin-1, 2, and 3 [1, 2]
We found that ET-1 production in normal endothelial cells was 25-fold higher than that from normal stellate cells (Fig. 2)
After liver injury, ET-1 release from stellate cells was increased, whereas it was decreased in sinusoidal endothelial cells
Summary
The family of endothelins is comprised of three 21-residue peptides, endothelin-1, 2, and 3 [1, 2]. The translational product of preproET-1 mRNA (preproET-1) is cleaved by as yet poorly identified furin-like enzymes to yield a peptide of 39 amino acid residues, which has been termed big ET-1 [1, 3]. This enzymatic step has been felt to be relatively nonspecific and not rate-limiting [1]. ET-1 production during hepatic wounding is likely to be regulated (at least in part) at the level of preproET-1 mRNA production in liver endothelial and stellate cells [13], we hypothesized that ECE-1 could be an important regulator of ET-1 production. The data are consistent with a unique combination of regulatory events in specific cellular compartments during hepatic wound healing and have important implications for endothelin biology in parenchymal organ injury
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