Abstract 028: Effects of N-acetyl-seryl-aspartyl-lysyl-proline on Inflammatory Cells During the Acute Stage of Myocardial Infarction

Abstract

Background: The natural peptide N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) decreases inflammation in chronic diseases such as hypertension and heart failure. The effects of Ac-SDKP on acute inflammatory responses during myocardial infarction (MI) are unknown. During the first 72 hours post-MI, neutrophils, M1 macrophages (pro-inflammatory), and M2 macrophages (pro-resolution) and the release of myeloperoxidase (MPO) and matrix metalloproteinases (MMP) play a role in the development of cardiac rupture which is an uncommon, but fatal complication. We hypothesize that in the acute stage of MI, Ac-SDKP decreases the incidence of cardiac rupture and mortality by preventing the infiltration of immune cells and by decreasing the activation of MPO and MMP. Methods: MI was induced by the ligation of the left descending coronary artery in C57 mice. Vehicle or Ac-SDKP (1.6 mg/kg/d) was infused via osmotic minipump. Cardiac immune cell infiltration was assessed by flow cytometry, cardiac MPO and MMP activities were measured at 24-48 hrs post-MI. The incidence of cardiac rupture and mortality was determined at 7 days post-MI. Neutrophil migration was studied in vitro by chemotaxis transwell assay. Results: In infarcted mice, Ac-SDKP decreased the incidence of cardiac rupture from 51.0% (26 of 51 animals) to 27.3% (12/44; p=0.015) and mortality from 56.9% (29/51) to 31.8% (14/44; p=0.019). Ac-SDKP also reduced the cardiac infiltration by the M1 macrophages (veh: 1,495±236 vs Ac-SKDP: 765±69 cells/heart, p=0.027), without affecting M2 macrophages. Ac-SDKP did not affect neutrophil and MPO activity in vivo and neither affected neutrophil chemotaxis in vitro . However, Ac-SDKP prevented the activation of MMP-9 (veh: 3,686±508 vs Ac-SDKP: 1,696±512 optical density units, p=0.029) in infarcted hearts. Conclusion: Ac-SDKP prevents cardiac rupture and mortality in acute MI. These protective effects of Ac-SDKP are associated with a decrease in pro-inflammatory M1 macrophage infiltration and MMP-9 activation. Perspective: Cardiac rupture is an uncommon, but fatal complication of MI that could be prevented by the administration of Ac-SDKP or a peptidase resistant analog.