Collagen C‐peptide roles in post‐myocardial infarction remodeling (867.15)

Collagen type I is the main extracellular protein present in the left ventricle (LV). The aim of this study was to determine the mechanisms whereby collagen peptide (C‐peptide 1158/9), initially generated by several proteases and later degraded by matrix metalloproteinase (MMP)‐9, mediates LV remodeling following myocardial infarction (MI). We performed cleavage assays of recombinant collagen type I by MMP‐2, ‐8, ‐9, and ‐11. MMP‐2, ‐8, and ‐9 all cleaved collagen, but only MMP‐2 and ‐9 formed peptides <24 kDa. Increased doses of MMP‐9 resulted in further degradation of the <24 kDa collagen peptides. The cleavage products were analyzed by mass spectrometry and the MMP‐2/9 cleavage site was identified (aa1158/9). In vitro, C‐peptide 1158/9 stimulated cardiac fibroblast wound healing, suggesting a role in cell migration. In vivo, we found higher levels of the C‐peptide in MMP‐9 null infarcted LV (LVI) at day 5 post‐MI compared to wild type, indicating accumulation of peptide in the absence of MMP‐9. C‐peptide 1158/9 in vivo treatment attenuated LV dysfunction at day 7 post‐MI, evidenced by higher ejection fraction compared to saline MI. In summary, C‐peptide 1158/9 improved LV function by stimulating the cardiac repair response. Grant Funding Source : Supported by POST14350034, HHSN 268201000036C, R01 HL075360, HL051971, 5I01BX000505