MMP‐9 Generated Collagen I C‐propeptides Alter Cardiac Fibroblast Function

Abstract

Heart failure is the result of adverse remodeling of the collagenous scar that replaces the damaged myocardium after myocardial infarction (MI). Post‐MI, specific matrix metalloproteinases (MMPs) increase and mediate left ventricle (LV) remodeling. Of the MMPs family members, MMP‐9 levels have been correlated with cardiovascular mortality in humans. Animal models show that MMP‐9 levels increase early post‐MI, and MMP‐9 deletion in mice attenuates remodeling. We found that C‐terminal propeptide (C‐propeptide) levels of á2(I) collagen were reduced in MMP‐9 null mice. Also, we have recently found a novel MMP‐9 recognition site that generates a C‐propeptide of 30 kDa.We used increasing doses of collagen fragments from the C‐terminus domain to stimulate cardiac fibroblasts and determine the mechanisms whereby C‐ propeptides regulate collagen function. We identified one fragment that strongly enhanced collagen I synthesis, suggesting a positive feedback loop between collagen processing and collagen synthesis. These results indicate that in addition to mediating ECM degradation, MMP‐9 may also regulate collagen I synthesis post‐MI.