title: Prolyl oligopeptidase is involved in release of the antifibrotic peptide Ac-SDKP.
abstract: N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a ubiquitous tetrapeptide hydrolyzed almost exclusively by angiotensin-converting enzyme (ACE). Chronic treatment with Ac-SDKP decreases cardiac and renal fibrosis and inflammatory cell infiltration in hypertensive rats. However, very little is known about endogenous synthesis of Ac-SDKP, except that thymosin-beta4 may be the most likely precursor. Two enzymes are potentially able to release Ac-SDKP from thymosin-beta4: prolyl oligopeptidase (POP) and endoproteinase asp-N. POP is widely present and active in several tissues and biological fluids, whereas endoproteinase asp-N appears to be lacking in mammals. Therefore, we hypothesized that POP is the main enzyme involved in synthesizing the antifibrotic peptide Ac-SDKP. We investigated in vitro and in vivo production of Ac-SDKP. Using kidney cortex homogenates, we observed that Ac-SDKP was generated in a time-dependent manner in the presence of exogenous thymosin-beta4, and this generation was significantly inhibited by several POP inhibitors (POPi), Z-prolyl-prolinal, Fmoc-prolyl-pyrrolidine-2-nitrile, and S17092. Long-term administration of S17092 in rats significantly decreased endogenous levels of Ac-SDKP in the plasma (from 1.76+/-0.2 to 1.01+/-0.1 nM), heart (from 2.31+/-0.21 to 0.83+/-0.09 pmol/mg protein), and kidneys (from 5.62+/-0.34 to 2.86+/-0.76 pmol/mg protein). As expected, ACE inhibitors significantly increased endogenous levels of Ac-SDKP in the plasma, heart, and kidney, whereas coadministration of POPi prevented this increase. We concluded that POP is the main enzyme responsible for synthesis of the antifibrotic peptide Ac-SDKP.
authors.affiliation: Hypertension and Vascular Research Division, Henry Ford Health System, 2799 West Grand Blvd, E&R 7115, Detroit, Mich 4820, USA. mcavasi1@hfhs.org
authors.forename: Maria A
authors.initials: MA
authors.lastname: Cavasin
authors.forename: Nour-Eddine
authors.initials: NE
authors.lastname: Rhaleb
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Yang
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Carretero
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002216:Captopril / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D007672:Kidney Cortex / Q000201:enzymology*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D009842:Oligopeptides / Q000032:analysis / Q000096:biosynthesis*; D009928:Organ Specificity; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D000085822:Prolyl Oligopeptidases; D011480:Protease Inhibitors / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D013947:Thymosin / Q000378:metabolism; D000099201:Thymosin beta(4)
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002216:Captopril; D004151:Dipeptides; D007211:Indoles; D009570:Nitriles; D009842:Oligopeptides; D011392:Proline; D000085822:Prolyl Oligopeptidases; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D013844:Thiazoles; D053778:Thiazolidines; D013947:Thymosin; D000099201:Thymosin beta(4); C491138:9-fluorenylmethoxycarbonyl-prolyl-pyrrolidine-2-nitrile; C118986:S 17092-1; C038541:N-benzyloxycarbonylprolylprolinal; C058504:goralatide