title: N-acetyl-Ser-Asp-Lys-Pro inhibits phosphorylation of Smad2 in cardiac fibroblasts.
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 beta(1) (TGFbeta1)-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 G0/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 TGFbeta1-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.
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, University of Maastricht, The Netherlands.
authors.forename: Saraswati
authors.initials: S
authors.lastname: Pokharel
authors.forename: Saman
authors.initials: S
authors.lastname: Rasoul
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: Roks
authors.forename: Rick E W
authors.initials: RE
authors.lastname: van Leeuwen
authors.forename: Marja J A
authors.initials: MJ
authors.lastname: van Luyn
authors.forename: Leo E
authors.initials: LE
authors.lastname: Deelman
authors.forename: Jos F
authors.initials: JF
authors.lastname: Smits
authors.forename: Oscar
authors.initials: O
authors.lastname: Carretero
authors.forename: Wiek H
authors.initials: WH
authors.lastname: van Gilst
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001692:Biological Transport / Q000187:drug effects; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005312:Fetal Blood / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects / Q000235:genetics; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D051899:Smad2 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
chemical_list: D004268:DNA-Binding Proteins; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; D051899:Smad2 Protein; C497784:Smad2 protein, rat; C508962:Tgfb1 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D008156:Luciferases; C058504:goralatide