Abstract 577: Matricryptin p1158/59 Improves Cardiac Function Post-myocardial Infarction by Reducing Adverse Remodeling

Abstract

Matricryptins are biologically active peptides, generated from extracellular matrix proteolysis, able to regulate cell function and survival. We recently identified a collagen-derived matricryptin (p1158/59) that gradually forms post-myocardial infarction (MI). In humans, p1158/59 plasma levels negatively correlate with left ventricle (LV) filling pressure, indicating that therapeutic elevation of this matricryptin could benefit functional remodeling. Previously, we showed p1158/59 binds to cardiac fibroblasts in vitro to stimulate migration and mice treated with p1158/59 for 7 days post-MI display reduced fibrosis, suggestive of reduced LV remodeling. Our goals were to establish the therapeutic effects of p1158/59 in long term cardiac remodeling and function using a rodent MI model. We used a murine permanent occlusion MI model (male and female C57Bl/6 mice, 4-6 months old, n=6/group) to assess the effects of p1158/59 treatment. Three hours after MI, mice received matricryptin (950 μg/day) or saline solution via an osmotic mini-pump for 28 days (D28). Parameters of cardiac remodeling and function were analyzed by serial echocardiography (D0, D14, D28) and LV remodeling gene arrays. As measured by ejection fraction (EF), matricryptin p1158/59 significantly blunted the reduction in cardiac function observed post-MI (saline 12% EF, p1158/59 31% EF, p=0.004). Additionally, p1158/59 reduced LV dilation displaying decreased end-systolic and end-diastolic volumes compared to controls (ESV p=0.014, EDV p=0.037). Similarly, internal diameter (ID) in diastole and systole were also reduced versus saline (IDd p=0.010, IDs p=0.014). Finally, we observed less tinning of the posterior wall (PW) in p1158/59-treated mice compared to vehicle controls (LVPWd p=0.018, LVPWs p=0.047). These results indicate that p1158/59 attenuated cardiac dysfunction and remodeling post-MI by preserving cardiac compliance and structure. Our data suggest that matricryptin p11/58/59 treatment reduces adverse remodeling post-MI resulting in improved cardiac function.