Matrix metalloproteinases as input and output signals for post-myocardial infarction remodeling

Abstract

Despite current optimal therapeutic regimens, approximately one in four patients diagnosed with myocardial infarction (MI) will go on to develop congestive heart failure, and heart failure has a high five-year mortality rate of 50%. Elucidating mechanisms whereby heart failure develops post-MI, therefore, is highly needed. Matrix metalloproteinases (MMPs) are key enzymes involved in post-MI remodeling of the left ventricle (LV). While MMPs process cytokine and extracellular matrix (ECM) substrates to regulate the inflammatory and fibrotic components of the wound healing response to MI, MMPs also serve as upstream signaling initiators with direct actions on cell signaling cascades. In this review, we summarize the current literature regarding MMP roles in post-MI LV remodeling. We also identify the current knowledge gaps and provide templates for experiments to fill these gaps. A more complete understanding of MMP roles, particularly with regards to upstream signaling roles, may provide new strategies to limit adverse LV remodeling.

Keywords: Extracellular matridomics; Extracellular matrix; MMP; Proteomics; Signaling; Systems biology.

Figure 1

Once a candidate MMP substrate is identified, cleavage can be confirmed using an in vitro assay consisting of the MMP and a recombinant of the candidate protein. Using mass spectrometry, the cleavage site(s) can be mapped. Once sites are known, comparing the literature for similar matricryptins will provide insights into putative functions. For example, fibronectin and laminin matricryptins have been studied extensively in the angiogenesis field.[83] To test for biological function, peptides 15-20 amino acids in length that are immediately upstream or downstream of the cleavage site can be commercially generated. If many cleavage sites exist, computational analysis can help to focus on the most likely candidates. Starting with in vitro cell-based assays is higher throughput and more cost effective and will eliminate candidates that have no activity on any cell type of interest (i.e., cardiomyocytes, leukocytes, fibroblasts, or endothelial cells). Using small peptides to test biological activities of naturally occurring fragments bypasses difficulties associated with larger peptide synthesis. A short peptide is easier to synthesize, purify, and concentrate, and a small size peptide limits response variability, which can occur with a longer peptide that may possess multiple activities. Using a small peptide increases the probability that an effect is a direct response to the sequence and not due to peptide structural properties.[92]