Accumulation of pepstatin in cultured endothelial cells and its effect on endothelin processing

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Aspartic acid proteases have been implicated in the processing of ET-1(1–39) to ET-1(1–21). To further understand the role of this class of enzymes in ET-1 synthesis, cultured vascular endothelial cells were incubated with pepstatin, and the accumulation of the inhibitor and its effect on the processing of ET-1(1–39) was examined. Pepstatin accumulated in the cells in a time-dependent manner, to a concentration (> 10 −7 M) sufficient to inhibit aspartic acid proteases. Pepstatin did not alter the ratio of ET-1(1–21) to ET-1(1–39), nor did it affect the rate of secretion of either peptide. When endothelial cells were incubated with phosphoramidon under identical conditions, the secretion of ET-1(1–21) was significantly reduced with a concomitant increase in the secretion of ET-1(1–39). These results suggest that the processing of ET-1(1–39) does not involve a pepstatin-sensitive aspartic acid protease, and that the enzyme responsible for generating ET-1(1–21) is sensitive to phosphoramidon.