Published Online
on March 22, 2004

A more recent version of this article appeared on May 1, 2004

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Submitted on December 1, 2003
Revised on December 30, 2003

Prolyl Oligopeptidase Is Involved in Release of the Antifibrotic Peptide Ac-SDKP

Maria A. Cavasin^*; Nour-Eddine Rhaleb; Xiao-Ping Yang; and Oscar A. Carretero

From the Hypertension and Vascular Research Division, Henry Ford Health System, Detroit, Mich.

^* To whom correspondence should be addressed. E-mail: mcavasi1{at}hfhs.org.

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-₄ may be the most likely precursor. Two enzymes are potentially able to release Ac-SDKP from thymosin-₄: 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-₄, 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.

Key words: angiotensin-converting enzyme • heart • kidney

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