Proteolytic processing pattern of the endothelin-1 precursor in vivo.
Endothelin-1 (ET-1) is a potent vasoconstrictor, which has been implicated in diseases involving dysfunctions of the cardiovascular system. For the biogenesis of ET-1, a larger precursor peptide (proET-1) is cleaved at two sites to give rise to bigET-1, which is subsequently cleaved to generate mature ET-1. In the present study, we investigated, which other peptides are derived from proET-1 in vivo. Six sandwich immunoassays covering various regions of proET-1 were developed and used to detect circulating proET-1 immunoreactivities in plasma of healthy subjects and septic patients. With this approach we could (a) demonstrate that, in addition to bigET-1/ET-1, three stable proET-1 fragments are generated, (b) exclude two previously discussed regions as sites for prohormone conversion and (c) show that the proteolytic processing pattern of proET-1 is unchanged under pathological conditions, which are associated with elevated levels of proET-1 fragments. The high stability and similarity in concentration of the proET-1 fragments suggest that these might be non-functional in the circulation. Stable proET-1 fragments maybe used in the future as reliable diagnostic targets to indirectly assess the release of ET-1, which might help to more selectively direct therapeutic measures.
Struck
Joachim
J
Department of Research, BRAHMS Aktiengesellschaft, Neuendorfstr. 25, D-16761 Hennigsdorf, Germany. j.struck@brahms.de
Morgenthaler
Nils G
NG
Bergmann
Andreas
A
D019332:Endothelin-1 / Q000097:blood* / Q000737:chemistry; D016232:Endothelins / Q000097:blood* / Q000737:chemistry; D006801:Humans; D010949:Plasma / Q000737:chemistry / Q000201:enzymology*; D011498:Protein Precursors / Q000097:blood* / Q000737:chemistry; D011499:Protein Processing, Post-Translational; D012772:Shock, Septic / Q000097:blood / Q000201:enzymology*
D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; C093240:proendothelin 1