title: Ac-SDKP reverses inflammation and fibrosis in rats with heart failure after myocardial infarction.
abstract: Inflammation may play an important role in the pathogenesis of cardiac fibrosis in heart failure (HF) after myocardial infarction (MI). N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring antifibrotic peptide whose plasma concentration is increased 4- to 5-fold by angiotensin-converting enzyme inhibitors. We tested the hypothesis that in rats with HF after MI, Ac-SDKP acts as an anti-inflammatory cytokine, preventing and also reversing cardiac fibrosis in the noninfarcted area (reactive fibrosis), and thus affording functional improvement. We found that Ac-SDKP significantly decreased total collagen content in the prevention group from 23.7+/-0.9 to 15.0+/-0.7 microg/mg and in the reversal group from 22.6+/-2.2 to 14.4+/-1.6 (P<0.01). Interstitial collagen volume fraction and perivascular collagen were likewise significantly reduced. We also found that infiltrating macrophages were reduced from 264.7+/-8.1 to 170.2+/-9.2/mm2, P<0.001 (prevention), and from 257.5+/-9.1 to 153.1+/-8.5 mm2, P<0.001 (reversal), while transforming growth factor (TGF)-beta-positive cells were decreased from 195.6+/-8.4 to 129.6+/-5.7/mm2, P<0.01 (prevention), and from 195.6+/-8.4 to 130.7+/-10.8/mm2, P<0.01 (reversal). Ac-SDKP did not alter either blood pressure or left ventricular hypertrophy (LVH); however, it depressed systolic cardiac function in the prevention study while having no significant effect in the reversal group. We concluded that Ac-SDKP has an anti-inflammatory effect in HF that may contribute to its antifibrotic effect; however, this decrease in fibrosis without changes in LVH was not accompanied by an improvement in cardiac function.
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Mich 48202-2689, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Yang
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Yang
authors.forename: Yun-He
authors.initials: YH
authors.lastname: Liu
authors.forename: Jiang
authors.initials: J
authors.lastname: Xu
authors.forename: Oscar
authors.initials: O
authors.lastname: Cingolani
authors.forename: Nour-Eddine
authors.initials: NE
authors.lastname: Rhaleb
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Carretero
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002303:Cardiac Output, Low / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000032:analysis; D005355:Fibrosis; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000517:prevention & control; D008264:Macrophages / Q000502:physiology; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D009206:Myocardium / Q000166:cytology / Q000276:immunology / Q000473:pathology; D009842:Oligopeptides / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D016212:Transforming Growth Factor beta / Q000032:analysis
chemical_list: D000893:Anti-Inflammatory Agents; D009842:Oligopeptides; D016212:Transforming Growth Factor beta; D003094:Collagen; C058504:goralatide