Ac-SDKP reverses cardiac fibrosis in rats with renovascular hypertension.
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-beta (TGF-beta) and/or connective tissue growth factor (CTGF). In 2-kidney, 1-clip (2K-1C) hypertensive rats, Ac-SDKP at 400 or 800 microg/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 microg/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-beta 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-beta and CTGF in the heart.
Peng
Hongmei
H
Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Mich 48202-2689, USA.
Carretero
Oscar A
OA
Brigstock
David R
DR
Oja-Tebbe
Nancy
N
Rhaleb
Nour-Eddine
NE
D000809:Angiotensins / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D001920:Bradykinin / Q000494:pharmacology; D003094:Collagen / Q000032:analysis; D055513:Connective Tissue Growth Factor; D005355:Fibrosis; D006352:Heart Ventricles / Q000737:chemistry / Q000378:metabolism; D006978:Hypertension, Renovascular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000473:pathology*; D009842:Oligopeptides / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000809:Angiotensins; C526316:CCN2 protein, rat; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009842:Oligopeptides; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D003094:Collagen; C058504:goralatide; D001920:Bradykinin