Ac-SDKP reverses inflammation and fibrosis in rats with heart failure after myocardial infarction.
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.
Yang
Fang
F
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Mich 48202-2689, USA.
Yang
Xiao-Ping
XP
Liu
Yun-He
YH
Xu
Jiang
J
Cingolani
Oscar
O
Rhaleb
Nour-Eddine
NE
Carretero
Oscar A
OA
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
D000893:Anti-Inflammatory Agents; D009842:Oligopeptides; D016212:Transforming Growth Factor beta; D003094:Collagen; C058504:goralatide