Abstract 16016: MMP-9 Generated Collagen I C-terminus Peptides Enhance Cardiac Fibroblast Wound Healing Response
In the myocardium, collagen is synthesized by cardiac fibroblasts as procollagen. Secreted procollagen is cleaved by proteinases generating N-terminal and C-terminal propeptides (CTPs). Matrix metalloproteinase-9 (MMP-9) levels increase early post-myocardial infarction (MI), and MMP-9 deletion in mice attenuates remodeling. As such, we compared the infarct proteome of wild type and MMP-9 null mice. We identified novel MMP-9 cleavage sites that generate collagen type I peptides from the C-terminal region and found reduced generation of CTPs in the MMP-9 null group. We hypothesized that an increase in MMP-9 generated CTPs may stimulate LV remodeling post-MI by activating pro-fibrotic responses. A recombinant procollagen was incubated with MMP-9 catalytic domain; the resulting products were analyzed by mass spectrometry. Detection of non-tryptic sites identified novel MMP-9 cleavage sites; cleavage product peptides were then synthesized to assess biological activity. Cardiac fibroblasts were isolated from WT mice and incubated with increasing doses of the peptides. While the collagen peptides did not show mitogenic activity, they did increase both the fibroblast wound healing response and collagen III synthesis. The results of our experiments demonstrated that MMP-9 cleaves collagen type I in the C-terminal region and the collagen peptides generated enhance the fibroblast wound healing response and secretion of collagen type III, which has important implications in the post-MI myocardium.
- © 2012 by American Heart Association, Inc.