Lindsey et al 2015 JACC.pdf

BACKGROUND Proteolytically released extracellular matrix (ECM) fragments, matricryptins, are biologically active and<br>play important roles in wound healing. Following myocardial infarction (MI), collagen I, a major component of cardiac<br>ECM, is cleaved by matrix metalloproteinases (MMPs).<br>OBJECTIVES This study identified novel collagen-derived matricryptins generated post-MI that mediate remodeling of<br>the left ventricle (LV).<br>METHODS Recombinant collagen Ia1 was used in MMPs cleavage assays, the products were analyzed by mass spectrometry for identification of cleavage sites. C57BL6/J mice were given MI and animals were treated either with vehicle control or p1158/59 matricryptin. Seven days post-MI, LV function and parameters of LV remodeling were measured. Levels of p1158/59 were also measured in plasma of MI patients and healthy controls.<br>RESULTS In situ, MMP-2 and -9 generate a collagen Ia1 C-1158/59 fragment, and MMP-9 can further degrade it. The<br>C-1158/59 fragment was identified post-MI, both in human plasma and mouse LV, at levels that inversely correlated to<br>MMP-9 levels. We synthesized a peptide beginning at the cleavage site (p1158/59, amino acids 1159 to 1173) to investigate its biological functions. In vitro, p1158/59 stimulated fibroblast wound healing and robustly promoted angiogenesis. In vivo, early post-MI treatment with p1158/59 reduced LV dilation at day 7 post-MI by preserving LV structure (p < 0.05 vs. control). The p1158/59 stimulated both in vitro and in vivo wound healing by enhancing basement membrane proteins, granulation tissue components, and angiogenic factors.<br>CONCLUSIONS Collagen Ia1 matricryptin p1158/59 facilitates LV remodeling post-MI by regulating scar formation through targeted ECM generation and stimulation of angiogenesis.