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Antifibrotic effect of Ac-SDKP and angiotensin-converting enzyme inhibition in hypertension
- Source :
- Journal of Hypertension, 22(3), 593-603. LIPPINCOTT WILLIAMS & WILKINS
- Publication Year :
- 2004
-
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. Design and methods Rats were divided into five groups: (1) controls, (2) Ang II (750 mug/kg per day, s.c.), (3) Ang II + captopril (100 mg/kg per day in drinking water), (4) Ang II + Ac-SDKP (400 mug/kg per day, s.c.), and (5) Ang II + Ac-SDKP (800 mug/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 mug/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 mug/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. (C) 2004 Lippincott Williams Wilkins.
- Subjects :
- Male
collagen
Captopril
RAT CARDIAC FIBROBLASTS
Physiology
TISSUE GROWTH-FACTOR
Angiotensin-Converting Enzyme Inhibitors
Blood Pressure
Kidney
Monocytes
Muscle hypertrophy
Rats, Sprague-Dawley
Fibrosis
Heart Rate
Transforming Growth Factor beta
Medicine
Myocytes, Cardiac
Mast Cells
N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP)
biology
INFLAMMATORY CELLS
TGF-BETA
Hematopoietic stem cell proliferation
Growth Inhibitors
angiotensin-converting enzyme inhibitor
STEM-CELL PROLIFERATION
Intercellular Signaling Peptides and Proteins
MAST-CELLS
Drug Therapy, Combination
Hypertrophy, Left Ventricular
Cardiology and Cardiovascular Medicine
Oligopeptides
Cell Division
medicine.drug
ASPARTYL-LYSYL-PROLINE
medicine.medical_specialty
hypertension
MYOCARDIAL FIBROSIS
heart
Article
Immediate-Early Proteins
Internal medicine
Renin–angiotensin system
Internal Medicine
Animals
COLLAGEN DEPOSITION
business.industry
Macrophages
Myocardium
Connective Tissue Growth Factor
Kidney metabolism
Angiotensin-converting enzyme
angiotensin
NEGATIVE REGULATOR
medicine.disease
Rats
Endocrinology
inflammation
ACE inhibitor
biology.protein
business
Subjects
Details
- Language :
- English
- ISSN :
- 02636352
- Database :
- OpenAIRE
- Journal :
- Journal of Hypertension, 22(3), 593-603. LIPPINCOTT WILLIAMS & WILKINS
- Accession number :
- edsair.doi.dedup.....0534af9efc2fb1f83224ca04362766b3