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PMID: 15076166 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Antifibrotic effect of Ac-SDKP and angiotensin-converting enzyme inhibition in hypertension.

Journal of hypertension ·Vol. 22 ·No. 3 ·2004-03-00 ·Pages 593-603

Rasoul S, Carretero OA, Peng H, Cavasin MA, Zhuo J, Sanchez-Mendoza A, Brigstock DR, Rhaleb NE

Abstract

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. 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. 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. 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.

MeSH Terms
Angiotensin-Converting Enzyme Inhibitors/pharmacology Animals Blood Pressure Captopril/pharmacology Cell Division/drug effects Collagen/metabolism Connective Tissue Growth Factor Drug Therapy, Combination Fibrosis Growth Inhibitors/pharmacology Heart Rate Hypertension/drug therapy,pathology Hypertrophy, Left Ventricular/drug therapy,pathology Immediate-Early Proteins/metabolism Intercellular Signaling Peptides and Proteins/metabolism Kidney/metabolism Macrophages/pathology Male Mast Cells/pathology Monocytes/pathology Myocardium/metabolism,pathology Myocytes, Cardiac/pathology Oligopeptides/blood,pharmacology Rats Rats, Sprague-Dawley Transforming Growth Factor beta/metabolism
Chemicals
Angiotensin-Converting Enzyme Inhibitors CCN2 protein, rat Growth Inhibitors Immediate-Early Proteins Intercellular Signaling Peptides and Proteins Oligopeptides Transforming Growth Factor beta Connective Tissue Growth Factor Collagen Captopril goralatide
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Rasoul Saman
University Hospital Groningen, The Netherlands.
Carretero Oscar A
Peng Hongmei
Cavasin Maria A
Zhuo Jialong
Sanchez-Mendoza Alicia
Brigstock David R
Rhaleb Nour-Eddine
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Article Info
Journal
Journal of hypertension
Abbr.
J Hypertens
ISSN
0263-6352
DOI
10.1097/00004872-200403000-00023
Published
2004-03-00
Pages
593-603
Language
English
Region
England
NLM ID
8306882
PMCID
PMC6824438
Subset
IM
Grants
NIDDK NIH HHS · R01 DK067299 · United States
NHLBI NIH HHS · R01 HL071806 · United States
NHLBI NIH HHS · HL 28982 · United States
NHLBI NIH HHS · HL 718060-01 · United States
External Links
PubMed source DOI: 10.1097/00004872-200403000-00023 PMC Full Text View journal details
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