title: Antifibrotic effect of Ac-SDKP and angiotensin-converting enzyme inhibition in hypertension.
abstract: OBJECTIVE
  N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a potent natural inhibitor of hematopoietic stem cell proliferation which is degraded mainly by angiotensin-converting enzyme (ACE). In vitro, Ac-SDKP inhibits collagen production by cardiac fibroblasts; while in vivo it blocks collagen deposition in the left ventricle (LV) of rats with hypertension or myocardial infarction (MI). In addition, it reportedly prevents and reverses macrophage infiltration in the LV of rats with MI. We tested the hypothesis that when Ac-SDKP is infused at doses that cause plasma concentrations similar to those observed after ACE inhibition, it mimics the anti-inflammatory and antifibrotic effects of ACE inhibitors (ACEi) in the heart, and, further, that these effects are independent of changes in blood pressure.
  
  
  METHODS
  Rats were divided into five groups: (1) controls, (2) Ang II (750 microg/kg per day, s.c.), (3) Ang II + captopril (100 mg/kg per day in drinking water), (4) Ang II + Ac-SDKP (400 microg/kg per day, s.c.), and (5) Ang II + Ac-SDKP (800 microg/kg per day, s.c.). We measured LV cell proliferation, inflammatory cell infiltration, cytokine expression, hypertrophy and fibrosis.
  
  
  RESULTS
  Plasma Ac-SDKP was five-fold higher in rats given ACEi and four- and ten-fold higher in rats given 400 and 800 microg/kg per day Ac-SDKP, respectively. ACEi significantly decreased Ang II-induced cell proliferation (Ki-67), LV macrophage/mast cell infiltration, transforming growth factor-beta, connective tissue growth factor and collagen deposition without affecting hypertension, LV hypertrophy or myocyte cross-sectional area, and these effects were mimicked by exogenous Ac-SDKP (400 microg/kg per day) which raised plasma Ac-SDKP to levels similar to ACEi. BP was not decreased by either ACEi or Ac-SDKP.
  
  
  CONCLUSIONS
  We concluded that Ac-SDKP may be an important mediator of the anti-inflammatory and antifibrotic effects of ACEi in hypertension independent of its hemodynamic effects.
authors.affiliation: University Hospital Groningen, The Netherlands.
authors.forename: Saman
authors.initials: S
authors.lastname: Rasoul
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Carretero
authors.forename: Hongmei
authors.initials: H
authors.lastname: Peng
authors.forename: Maria A
authors.initials: MA
authors.lastname: Cavasin
authors.forename: Jialong
authors.initials: J
authors.lastname: Zhuo
authors.forename: Alicia
authors.initials: A
authors.lastname: Sanchez-Mendoza
authors.forename: David R
authors.initials: DR
authors.lastname: Brigstock
authors.forename: Nour-Eddine
authors.initials: NE
authors.lastname: Rhaleb
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D002216:Captopril / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D004359:Drug Therapy, Combination; D005355:Fibrosis; D006131:Growth Inhibitors / Q000494:pharmacology*; D006339:Heart Rate; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000473:pathology; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000473:pathology; D009000:Monocytes / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D009842:Oligopeptides / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; C526316:CCN2 protein, rat; D006131:Growth Inhibitors; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009842:Oligopeptides; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D003094:Collagen; D002216:Captopril; C058504:goralatide