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Collagen Production in Cardiac Fibroblasts During Inhibition of Aminopeptidase B

Hypertension and Cardiovascular Rehabilitation Unit, Department of Cardiovascular Diseases, Katholieke Universiteit Leuven (K.U.Leuven), Belgium, paul.lijnen{at}med.kuleuven.ac.be

Victor V Petrov

Hypertension and Cardiovascular Rehabilitation Unit, Department of Cardiovascular Diseases, Katholieke Universiteit Leuven (K.U.Leuven), Belgium

Marisa Turner

Hypertension and Cardiovascular Rehabilitation Unit, Department of Cardiovascular Diseases, Katholieke Universiteit Leuven (K.U.Leuven), Belgium

Robert H Fagard

Hypertension and Cardiovascular Rehabilitation Unit, Department of Cardiovascular Diseases, Katholieke Universiteit Leuven (K.U.Leuven), Belgium

Objective. To determine whether the aminopeptidase B inhibitor, arphamenine A, could affect collagen production and expression in control and TGF-ß₁-treated cardiac fibroblasts.

Design and Methods. Cardiac fibroblasts from passage 2 from normal male adult rats were cultured to confluency and incubated with and without 600 pmol/l TGF-ß₁ for 2 days in serum-free Dulbecco's modified Eagle's medium and then incubated with 100 µmol/l arphamenine A for 1 day in this medium added ascorbic acid, ß-aminopropionitrile and titriated proline. Soluble collagen was measured in the conditioned medium and non-soluble collagen in the cell layer. Aminopeptidase activity was estimated by spectrophotometric determination of the liberation of p-nitroaniline from alanine- or arginine-p-nitroanilide. Matrix metalloproteinase (MMP) and lysyl oxidase activity were assayed in the conditioned medium. A semi-quantitative reverse transcriptase- polymerase chain reaction was used to examine the expression of lysyl oxidase and collagen type I and III. Results. Arphamenine A dose-dependently

inhibited basal and TGF-ß ₁-stimulated aminopeptidase activity. Arphamenine A reduced soluble and non-soluble collagen production in control and TGF-ß₁-treated cardiac fibroblasts, while it decreased collagen type I and III expression only in TGF-ß₁-treated fibroblasts. Lysyl oxidase, MMP-1 and MMP-2 activity were inhibited by arphamenine A in the conditioned media of control and TGF-ß₁treated cardiac fibroblasts.

Conclusions. Our data show that the specific aminopeptidase B inhibitor, arphamenine A, reduces collagen production in cardiac fibroblasts and that this reduction is accompanied by a pronounced inhibition of lysyl oxidase.

Key Words: Collagen production • Aminopeptidase B • Cardiac fibroblasts

Journal of Renin-Angiotensin-Aldosterone System, Vol. 6, No. 2, 69-77 (2005)
DOI: 10.3317/jraas.2005.012


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