Published Online
on October 27, 2003

A more recent version of this article appeared on December 1, 2003

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Submitted on June 27, 2003
Revised on July 21, 2003

Ac-SDKP Reverses Cardiac Fibrosis in Rats With Renovascular Hypertension

Hongmei Peng; Oscar A. Carretero; David R. Brigstock; Nancy Oja-Tebbe; and Nour-Eddine Rhaleb^*

From the Hypertension and Vascular Research Division (H.P., O.A.C., N.-E.R.) and the Department of Biostatistics and Research Epidemiology (N.O.-T.), Henry Ford Hospital, Detroit, Mich; and the Department of Surgery (D.R.B.), Children’s Hospital and Ohio State University, Columbus, Ohio.

^* To whom correspondence should be addressed. E-mail: nrhaleb1{at}hfhs.org.

Abstract--N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural substrate for the N-terminal active site of angiotensin-converting enzyme (ACE). We previously reported that Ac-SDKP prevented cardiac fibrosis in rats with renovascular or aldosterone-salt hypertension. However, it is not clear whether Ac-SDKP reverses cardiac fibrosis in hypertension, nor the mechanism(s) involved. In the present study, we tested the hypothesis that Ac-SDKP reversal of hypertension-induced cardiac fibrosis involves a decrease in transforming growth factor- (TGF-) and/or connective tissue growth factor (CTGF). In 2-kidney, 1-clip (2K-1C) hypertensive rats, Ac-SDKP at 400 or 800 µg/kg per day SC was started 8 weeks after hypertension and cardiac fibrosis were established and was continued for 8 weeks. Left ventricular (LV) collagen in rats with 2K-1C plus vehicle at 8 and 16 weeks after clipping was similar but higher than in the sham group (P<0.05). Ac-SDKP at 400 and 800 µg/kg per day, which increased plasma Ac-SDKP 2- and 5-fold, respectively, reversed the increase in LV collagen in a dose-dependent manner. The mechanism by which Ac-SDKP reverses LV fibrosis does not appear to depend on ACE inhibition by Ac-SDKP, since we found that Ac-SDKP at various doses did not affect blood pressure responses to exogenous angiotensin I or bradykinin. However, Ac-SDKP reversed the increase in LV TGF- and CTGF compared with rats with 2K-1C plus vehicle (P<0.005). We concluded that in hypertension, Ac-SDKP reverses cardiac fibrosis, perhaps due in part to a decrease in TGF- and CTGF in the heart.

Key words: hypertension, renovascular • collagen • heart • fibrosis • transforming growth factors

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