Phosphoramidon‐sensitive endothelin‐converting enzyme in vascular endothelial cells converts big endothelin‐1 and big endothelin‐3 to their mature form

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Abstract
Incubation of big endothelin‐3 (big ET‐31–41) with the membrane fraction obtained from cultured endothelial cells (ECs) resulted in an increase in immunoreactive‐ET (IR‐ET). This increasing activity was markedly suppressed by phosphoramidon, which is known to inhibit the conversion of big ET‐11–39 to ET‐11–21. Reverse‐phase HPLC of the incubation mixture of the membrane fraction with big ET‐3 revealed one major IR‐ET component corresponding to the elution position of synthetic ET‐31–21. When the cultured ECs were incubated with big ET‐3, a conversion to the mature ET‐3, as well as an endogenous ET‐1 generation, was observed. Both responses were markedly suppressed by phosphoramidon. By the gel filtration of 0.5% CHAPS‐solubilized fraction of membrane pellets or ECs, the molecular mass of the proteinase which converts big ET‐1 and big ET‐3 to their mature form was estimated to be 300–350 kDa. Phosphoramidon almost completely abolished both converting activities of the proteinase. We conclude that the above type of phosphoramidon‐sensitive metalloproteinase functions as an ET‐converting enzyme to generate the mature form from big ET‐1 and big ET‐3 in ECs.

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