Abstract 12780: Collagen Derived Matricryptin Robustly Promotes Angiogenesis Post-myocardial Infarction Reducing Cardiac Dysfunction

Abstract

Proteolytically released extracellular matrix (ECM) fragments - matricryptins - exert biological activities usually different from those of the full-length protein and play important roles in tissue healing and regeneration. Following myocardial infarction (MI), the native ECM is cleaved by proteases during remodeling of the left ventricle (LV) originating ECM-derived peptides. Previously, we identified a collagen matricryptin, p1158/59, that is naturally generated post-MI. This study aimed to identify the biological roles of this matricryptin. We isolated cardiac fibroblasts from mouse hearts and treated cells with 1 μM of p1158/59. HUVEC cells were used to assess p1158/59 effects in angiogenesis. A permanent occlusion model of MI was used to investigate the roles of p1158/59 in post-MI remodeling. Animals were treated with p1158/59 (950 μg/day/kg body weight) or saline for 7 days post-MI. In vitro, p1158/59 increased migration of cardiac fibroblasts and robustly induced formation of a network of 3-D capillary-like tubular structures in endothelial cells (~4-fold versus negative control, p<0.05). In vivo, mice treated with p1158/59 for 7 days post-MI showed enhanced expression of components of the basal membrane known to stimulate angiogenesis - Col4a1, Col4a2, and Lama1 (p<0.05 for all). By immunoblotting and immunohistochemistry we observed increased vessel numbers in both the remote and infarct regions of p1158/59 treated animals compared to those treated with saline (p<0.05). Increased angiogenesis in both remote and infarct regions may offer the necessary cardioprotection to mitigate the detrimental effects of hypoxia and resulting LV dysfunction post-MI. We used echocardiography to assess physiological effects. Animals treated with p1158/59 displayed preserved LV wall thickness, geometry, and contractility, resulting in reduced systolic dysfunction post-MI. Taken together, our data show that p1158/59 is a biologically active molecule with potent pro-angiogenic properties and strongly promote this matricryptin as a molecule of interest for treatment of adverse LV remodeling.