Published Online
on July 1, 2002

A more recent version of this article appeared on August 1, 2002

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Submitted on May 15, 2002
Revised on May 31, 2002

N-Acetyl-Ser-Asp-Lys-Pro Inhibits Phosphorylation of Smad2 in Cardiac Fibroblasts

Saraswati Pokharel; Saman Rasoul; Anton J.M. Roks; Rick E.W. van Leeuwen; Marja J.A. van Luyn; Leo E. Deelman; Jos F. Smits; Oscar Carretero; Wiek H. van Gilst; and Yigal M. Pinto^*

From the Department of Cardiology (S.P., R.E.W.v.L., Y.M.P.) and Department of Pharmacology (J.S.), Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, The Netherlands; GUIDE Research Institute, University of Groningen (A.J.M.R., M.J.A.v.L., L.E.D., W.H.v.G.), The Netherlands; and Hypertension and Vascular Research Division, Henry Ford Hospital (S.R., O.C.), Detroit, Mich.

^* To whom correspondence should be addressed. E-mail: ypi{at}cardio.azm.nl.

Abstract—N-Acetyl-Ser-Asp-Lys-Pro (AcSDKP) is a specific substrate for the N-terminal site of ACE and increases 5-fold during ACE inhibitor therapy. It is known to inhibit the proliferation of hematopoietic stem cells and has also recently been reported to inhibit the growth of cardiac fibroblasts. We investigated its mode of action in cardiac fibroblasts by assessing its influence on transforming growth factor ß₁ (TGFß1)--mediated Smad signaling. AcSDKP inhibited the proliferation of isolated cardiac fibroblasts (P<0.05) but significantly stimulated the proliferation of vascular smooth muscle cells. Flow cytometry of rat cardiac fibroblasts treated with AcSDKP showed significant inhibition of the progression of cells from G/G₁ phase to S phase of the cell cycle. In cardiac fibroblasts transfected with a Smad-sensitive luciferase reporter construct, AcSDKP decreased luciferase activity by 55±9.7% (P=0.01). Moreover, phosphorylation and nuclear translocation of Smad2 was decreased in cardiac fibroblasts treated with AcSDKP. To conclude, AcSDKP inhibits the growth of cardiac fibroblasts and also inhibits TGFß1-stimulated phosphorylation of Smad2. Because AcSDKP increases substantially during ACE inhibitor therapy, this suggests a novel pathway independent of angiotensin II, by which ACE inhibitors can inhibit cardiac fibrosis.

Key words: angiotensin • inhibitors • fibroblasts • transforming growth factors • myocardium

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