(Hypertension. 2001;37:827.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Effect of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline on DNA and Collagen Synthesis in Rat Cardiac Fibroblasts
From the Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Mich.
Correspondence to Nour-Eddine Rhaleb, PhD, Education and Research Suite 7015, Henry Ford Hospital, Hypertension and Vascular Research Division, 2799 West Grand Boulevard, Detroit, MI 48202-2689. E-mail nrhaleb1{at}hfhs.org
N-Acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural inhibitor of pluripotent hematopoietic stem cell entry into the S phase of the cell cycle and is normally present in human plasma. Ac-SDKP is exclusively hydrolyzed by ACE, and its plasma concentration is increased 5-fold after ACE inhibition in humans. We examined the effect of 0.05 to 100 nmol/L Ac-SDKP on 24-hour 3H-thymidine incorporation (DNA synthesis) by cardiac fibroblasts both in the absence and presence of 5% FCS. Captopril (1 µmol/L) was added in all cases to prevent the degradation of Ac-SDKP. Treatment of cardiac fibroblasts with 5% FCS increased thymidine incorporation from a control value of 12 469±594 to 24 598±1051 cpm (P<0.001). Cotreatment with 1 nmol/L Ac-SDKP reduced stimulation to control levels (10 373±200 cpm, P<0.001). We measured hydroxyproline content and incorporation of 3H-proline into collagenous fibroblast proteins and found that Ac-SDKP blocked endothelin-1 (10-8 mol/L)–induced collagen synthesis in a biphasic and dose-dependent manner, causing inhibition at low doses, whereas high doses had little or no effect. It also blunted the activity of p44/p42 mitogen-activated protein kinase in a biphasic and dose-dependent manner in serum-stimulated fibroblasts, suggesting that the inhibitory effect of DNA and collagen synthesis may depend in part on blocking mitogen-activated protein kinase activity. Participation of p44/p42 in collagen synthesis was confirmed, because a specific inhibitor for p44/p42 activation (PD 98059, 25 µmol/L) was able to block endothelin-1–induced collagen synthesis, similar to the effect of Ac-SDKP. The fact that Ac-SDKP inhibits DNA and collagen synthesis in cardiac fibroblasts suggests that it may be an important endogenous regulator of fibroblast proliferation and collagen synthesis in the heart. Ac-SDKP may participate in the cardioprotective effect of ACE inhibitors by limiting fibroblast proliferation (and hence collagen production), and therefore it would reduce fibrosis in patients with hypertension.
Key Words: amino acid • angiotensin-converting enzyme inhibitors • fibroblasts • collagen • endothelin • protein kinases
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