© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Angiotensin II AT1-receptor induces biglycan in neonatal cardiac fibroblasts via autocrine release of TGFβ in vitro
aInstitute of Pharmacology, Christian-Albrechts-University, Kiel, Germany
bInstitute of Pharmacology and Toxicology, Charité, Humbold University, Berlin, Germany
cResearch Unit Molecular Oncology, Clinic for General Surgery and Thoracic Surgery, Christian-Albrechts-University, Kiel, Germany
d1st Department of Medicine, Christian-Albrechts-University, Kiel, Germany
eMolecular Pharmacology, Institute of Pharmacology and Clinical Pharmacology, Heinrich-Heine-University, Moorenstrasse 5, D-40225 Düsseldorf, Germany
*Corresponding author. Tel.: +49-211-81-12513/12500; fax: +49-211-81-14781. Email address: jens.fischer{at}uni-duesseldorf.de
Objective: After myocardial infarction, angiotensin II (AngII) promotes ventricular remodeling and deposition of extracellular matrix (ECM), e.g., collagen type 1 and 3. Whether AngII regulates the expression of small leucine-rich proteoglycans (SLRP) which are important modulators of collagen fibrillogenesis and are induced after experimental myocardial infarction in rats is not known. The aim of the present study was therefore to analyse in cultured cardiac fibroblasts the expression and secretion of the SLRP biglycan in response to AngII. Methods: Cardiac fibroblasts were isolated from neonatal Wistar Kyoto rats and used in the first passage. Expression of AT1- and AT2-receptors was verified by RT-PCR. Expression of protoeglycans was analyzed after metabolic labeling with [35S]-sulfate, by SDS-PAGE and Western analysis. In addition, mRNA expression was examined by means of RT-PCR and Northern analysis. The activity of the biglycan promoter was analyzed using three biglycan promoter–luciferase fusion constructs. Results: Biglycan was found to be the predominant proteoglycan produced by neonatal cardiac fibroblasts in vitro. In response to AngII (10–7 M), secretion of total [35S]-labeled proteoglycans and mRNA of biglycan were increased to 116±1.8% and 121±11% (n = 5, mean±S.E.M.) of unstimulated controls, respectively. Biglycan induction in response to AngII was sensitive to Losartan (10–5 M) and unaffected by PD123177 (10–6 M), suggesting that the AT1-receptor mediates the induction of biglycan. Direct activation of the biglycan promoter downstream of the AT1-receptor was excluded by promoter activity assays. Instead, increased release of transforming growth factor beta 1 (TGFβ1) was detected by ELISA in response to AT1-receptor stimulation. Furthermore, neutralising antibodies to TGFβ1 inhibited biglycan induction in response to AngII. Conclusion: The results indicate that in cardiac fibroblasts AngII via the AT1-receptor causes autocrine release of TGFβ1, which in turn induces biglycan expression and secretion.
KEYWORDS Small leucine-rich proteoglycan; Fibrosis; Cardiac remodeling; Collagen; Decorin; Myocardial infarction
Abbreviations: AngII, angiotensin II • ECM, extracellular matrix • SLRP, small leucine-rich proteoglycan • GAG, glycosaminoglycan • TGFβ1, transforming growth factor beta1 • ACE, angiotensin-converting enzyme • bFGF, basic fibroblast growth factor • PDGF-BB, platelet-derived growth factor BB • CPC, cetylpyridinium chloride
Time for primary review 25 days
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