Published Online
on November 1, 2004

A more recent version of this article appeared on November 9, 2004

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Submitted on February 19, 2004
Revised on July 7, 2004
Accepted on August 10, 2004

Increased Myocardial Collagen Content in Transgenic Rats Overexpressing Cardiac Angiotensin-Converting Enzyme Is Related to Enhanced Breakdown of N-Acetyl-Ser-Asp-Lys-Pro and Increased Phosphorylation of Smad2/3

Saraswati Pokharel MBBS, Peter P. van Geel MD, PhD, Umesh C. Sharma MBBS, Jack P.M. Cleutjens PhD, Holger Bohnemeier PhD, Xiao-Li Tian PhD, Heribert Schunkert MD, Harry J.G.M. Crijns MD, PhD, Martin Paul MD, and Yigal M. Pinto MD, PhD^*

From Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht (CARIM) (S.P., U.C.S., H.J.G.M.C., Y.M.P.), and the Department of Pathology (J.P.M.C.), University Hospital Maastricht, Maastricht, and the Department of Cardiology, University Hospital Groningen, Groningen (P.P.v.G.), the Netherlands; the Institute of Clinical Pharmacology, Charite University Medical School, Berlin (H.B., M.P.), and the University of Lübeck, Lübeck (H.S.), Germany; and the Center for Molecular Genetics, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio (X.-L.T.).

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

Background--Although increased activity of angiotensin-converting enzyme (ACE) has been associated with increased cardiac collagen, no studies to date have established a direct cause-and-effect relation between the two.

Methods and Results--We used transgenic rats that overexpress human ACE selectively in the myocardium. Two independent heterozygous transgenic rat lines were studied, one expressing 2 to 3 copies (L1172) and the other expressing 5 to 10 copies (L1173) of the ACE transgene. These rats were normotensive but developed a proportionate increase in myocardial collagen depending on the ACE gene dose (up to 2.5-fold, P<0.01), but cardiac angiotensin II levels remained normal, whereas collagen content reversed to control levels on ACE inhibition. To explain these changes, we investigated N-acetyl-Ser-Asp-Lys-Pro (AcSDKP), an alternative substrate that is catabolized exclusively by ACE. Increased cardiac expression of ACE was paralleled by a reciprocal decrease in cardiac AcSDKP and a proportionate increase in phosphorylated Smad2 and Smad3, all of which normalized after both ACE inhibition and AcSDKP infusion. Furthermore, a functional link of this signaling cascade was demonstrated, because AcSDKP inhibited Smad3 phosphorylation in a dose-dependent manner in cultured cardiac fibroblasts and in vivo.

Conclusions--Our findings suggest that increased cardiac ACE activity can increase cardiac collagen content by degradation of AcSDKP, an inhibitor of the phosphorylation of transforming growth factor- signaling molecules Smad2 and Smad3. This implies that the antifibrotic effects of ACE inhibitors are mediated in part by increasing cardiac AcSDKP, with subsequent inhibition of Smad 2/3 phosphorylation.

Key words: enzymes • hypertrophy • myocardium • peptides

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