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. Uncontrolled ECM degradation exacerbates inflammation and uncontrolled deposition leads to a fibrotic, stiff myocardium. 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 processes. We recently identified an ECM-derived peptide (p1158/59) that acts as a competitive and specific MMP-9 substrate. Herein, we propose use of p1158/59 as an MMP-9 competitive substrate to reduce MMP-9 proteolytic capacity post-MI. This approach does not inhibit MMP-9 activity but rather limits its proteolytic capacity and therefore reduces cleavage of endogenous substrates that promote inflammation and inhibit repair. The synthetic peptide p1158/59 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 p1158/59 post-MI display less LV dilation, reduced inflammation and fibrosis, and improved cardiac function. While we know that exogenous delivery is beneficial, how p1158/59 regulates post-MI inflammation and ECM deposition has not been mechanistically dissected. Accordingly, the central hypothesis of this proposal is that p1158/59 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 p1158/59 in the post-MI setting, we propose to identify the mechanisms whereby p1158/59 tempers the post-MI inflammatory response, modulates cardiac fibroblast signaling to reduce ECM secretion; and promotes macrophage-fibroblast crosstalk.
Despite current therapies, the 5-year mortality after myocardial infarction (MI, commonly known as heart attack) is 40% due to adverse remodeling of the left ventricle (LV). We discovered a collagen-derived peptide that significantly reduces adverse remodeling post-MI by changing the inflammatory profile and directly interacting with reparative cells. This proposal will study the mechanisms underlying the peptide mode of action to explore new therapeutic avenues and, therefore, enhance our fundamental knowledge on the mechanisms of adverse LV remodeling.
