Myocardial infarction (MI) leads to the generation of a scar that is mostly constituted by cardiac extracellular
matrix (ECM). The balance between degradation and deposition of ECM is a strong predictor of clinical
outcomes. ECM degradation occurs by matrix metalloproteinases (MMPs); and ECM deposition occurs by
cardiac fibroblasts. Both ECM degradation and deposition promote adverse remodeling and progression to heart
failure. Within the MMP family, MMP-9 has been reported as a prognostic indicator of cardiac dysfunction in
myocardial infarction (MI) patients; as MMP-9 levels directly associate with patient mortality. Thus, the advantage
of inhibiting MMP-9 after MI has been long recognized. However, clinical trials using global MMP-9 inhibition
have mostly failed both due to lack of MMP inhibitor specificity and importance of MMP-9 in several essential
We recently identified an ECM-derived peptide (p1159) that acts as a competitive and specific MMP-9 substrate.
Herein, we propose use of p1159 to modulate MMP-9 cleavage of native substrates post-MI. This approach does
not inhibit MMP-9 activity, allowing it to participate in essential processes; instead, it modulates MMP-9
proteolytic capacity to reduce cleavage of endogenous substrates that promote inflammation and inhibit repair.
The synthetic peptide p1159 is a mimetic of the naturally formed fragment C-1158/59 generated by MMP-9
cleavage of collagen post-MI. In humans, plasma levels of endogenous C-1158/59 post-MI correlate with lower
left ventricle filling pressure, indicating a therapeutic potential of C-1158/59. Indeed, mice treated with exogenous
p1159 post-MI display less LV dilation, reduced inflammation and fibrosis, and improved cardiac function. In
vitro, we identified integrin a4 (Itga4) as a peptide receptor. While we know that exogenous delivery is beneficial,
how p1159 regulates post-MI inflammation and ECM deposition has not been mechanistically dissected.
Accordingly, the central hypothesis of this proposal is that p1159 blunts adverse remodeling after MI by serving
as a competitive substrate to reduce MMP-9 proteolysis of substrates necessary for promotion of inflammation
and ECM deposition. To elucidate the mode-of-action and signaling pathways mediated by p1159 in the post-MI
setting, we will use cell-specific Itga4 transgenic animals to identify the mechanisms whereby p1159 tempers
the post-MI inflammatory response, modulates cardiac fibroblast signaling to reduce ECM secretion; and
promotes macrophage-fibroblast crosstalk.