Characterisation of preproendothelin-1 derived peptides identifies Endothelin-Like Domain Peptide as a modulator of Endothelin-1

• Published in: Scientific reports 2017-07, Vol.7 (1), p.4956-15, Article 4956
• Main Authors: Yuzugulen, Jale, Douthwaite, Julie A., Wood, Elizabeth G., Villar, Inmaculada C., Patel, Nimesh S. A., Jegard, James, Gaertner, Hubert, Rossitto-Borlat, Irène, Rose, Keith, Hartley, Oliver, Cutillas, Pedro R., Ahluwalia, Amrita, Corder, Roger
• Format: Article
• Language: English
• Subjects: 13; 59; 692/4019/592; 692/53; 82; 82/1; 82/58; 82/83; A549 Cells; Amino acids; Arteries; Biological activity; Biological effects; Biomarkers - blood; Blood pressure; Cancer; Cell Line; Chromatography, Liquid; Conserved sequence; Coronary artery disease; Culture Media, Conditioned - chemistry; Culture Media, Conditioned - pharmacology; Endothelial cells; Endothelial Cells - cytology; Endothelial Cells - metabolism; Endothelin 1; Endothelin-1 - chemistry; Endothelin-1 - metabolism; Evolutionary conservation; Heart diseases; Heart Failure - diagnosis; Heart Failure - metabolism; Humanities and Social Sciences; Humans; Immunoassays; Injections, Intravenous; Kidney transplantation; multidisciplinary; Pathogenesis; Peptide Fragments - administration & dosage; Peptide Fragments - chemical synthesis; Peptide Fragments - chemistry; Peptide Fragments - pharmacokinetics; Peptides; Protein Precursors - chemistry; Rodents; Science; Science (multidisciplinary); Tandem Mass Spectrometry; Tumors; Vasoconstriction
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-05365-2

Endothelin-1 (ET-1) is involved in the pathogenesis of cardiac and renal diseases, and in the progression of tumour growth in cancer, but current diagnosis and treatment remain inadequate. Peptides derived from the 212 amino acid precursor preproendothelin-1 (ppET-1) may have utility as biomarkers, or cause biological effects that are unaffected by endothelin receptor antagonists. Here, we used specific immunoassays and LC-MS/MS to identify NT-proET-1 (ppET-1 [18–50] ), Endothelin-Like Domain Peptide (ELDP, ppET-1 [93–166] ) and CT-proET-1 (ppET-1 [169–212] ) in conditioned media from cultured endothelial cells. Synthesis of these peptides correlated with ET-1, and plasma ELDP and CT-proET-1 were elevated in patients with chronic heart failure. Clearance rates of NT-proET-1, ELDP and CT-proET-1 were determined after i.v . injection in anaesthetised rats. CT-proET-1 had the slowest systemic clearance, hence providing a biological basis for it being a better biomarker of ET-1 synthesis. ELDP contains the evolutionary conserved endothelin-like domain sequence, which potentially confers biological activity. On isolated arteries ELDP lacked direct vasoconstrictor effects. However, it enhanced ET-1 vasoconstriction and prolonged the increase in blood pressure in anaesthetised rats. ELDP may therefore contribute to disease pathogenesis by augmenting ET-1 responses.