Research Project
10241717
Abstract 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.
