Abstract Body: Matrix metalloproteinases (MMPs) play critical roles post-myocardial infarction (MI) and directly correlate with adverse LV remodeling. Of the MMPs, MMP-9 shows the highest correlation with MI patient mortality. Clinical trials trying to inhibit MMP-9 were unsuccessful or detrimental, mostly because MMP-9 has critical roles post-MI and inhibition results in exacerbation of adverse remodeling. Previously, we reported a collagen peptide – p1159 – to reduce LV dilation and adverse LV remodeling post-MI. Recently, we discovered p1159 acts as an MMP-9 competitive substrate and reduces substrate proteolysis in vitro. Herein, we investigated whether p1159 can act as a competitive substrate in vivo to reduce proteolysis of endogenous substrates post-MI without inhibiting MMP-9 activity. Also, we compared p1159 actions to those of a MMP-9 inhibitor (MMP-9i). We hypothesized that animals that receive p1159 would show reduced inflammation and adverse remodeling compared to those that received MMP-9i. Adult male and female C57Bl/6 mice (n = 6-8/group) were grouped as follows: saline (control); p1159; MMP-9i, and p1159 + MMP-9i. We performed baseline echocardiography followed by surgery to induce a permanent occlusion MI model. Three hours later, mice received a randomized osmotic mini-pump to continuously deliver p1159 (14μg/day/kg body weight) or vehicle (saline, 0.9%) and/or MMP-9i (10mg/kg body weight, JNJ 0966 by gavage). The LV and plasma were harvested on day 3 (D3) and D5 for downstream proteomics analysis following a final echocardiographic assessment. Infarct sizes were similar between groups, indicating same level of initial injury. Compared to control, p1159 did not inhibit activity or levels of MMP-9, while animals treated with MMP-9i showed significantly reduced MMP-9 activity. As expected, p1159 reduced (p < 0.05) substrate cleavage, as seen by analysis of the LV peptidome, particularly at D3. Substrates that displayed a reduction in proteolysis included fibrinogen, MIF, myosin, titin, and tubulin. These data support p1159 as a competitive substrate of MMP-9 that can modulate its activity without inhibition. Moreover, these results may explain the previously reported effect of p1159 at reducing LV dilation and improving systolic function.