A Novel Collagen Matricryptin Reduces Left Ventricular Dilation Post-Myocardial Infarction by Promoting Scar Formation and Angiogenesis

Merry L. Lindsey, Rugmani Padmanabhan Iyer, Rogelio Zamilpa, Andriy Yabluchanskiy, Kristine Y. DeLeon-Pennell, Michael E. Hall, Abdullah Kaplan, Fouad A. Zouein, Dustin Bratton, Elizabeth R. Flynn, Presley L. Cannon, Yuan Tian, Yu Fang Jin, Richard A. Lange, Dorota Tokmina-Roszyk, Gregg B. Fields, Lisandra E. De Castro Brás

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

Background Proteolytically released extracellular matrix (ECM) fragments, matricryptins, are biologically active and play important roles in wound healing. Following myocardial infarction (MI), collagen I, a major component of cardiac ECM, is cleaved by matrix metalloproteinases (MMPs). Objectives This study identified novel collagen-derived matricryptins generated post-MI that mediate remodeling of the left ventricle (LV). 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. Results In situ, MMP-2 and -9 generate a collagen Iα1 C-1158/59 fragment, and MMP-9 can further degrade it. The C-1158/59 fragment was identified post-MI, both in human plasma and mouse LV, at levels that inversely correlated to 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. Conclusions Collagen Iα1 matricryptin p1158/59 facilitates LV remodeling post-MI by regulating scar formation through targeted ECM generation and stimulation of angiogenesis.

Original languageEnglish (US)
Pages (from-to)1364-1374
Number of pages11
JournalJournal of the American College of Cardiology
Volume66
Issue number12
DOIs
StatePublished - Sep 22 2015

    Fingerprint

Keywords

  • Key Words collagen
  • MMP
  • extracellular matrix
  • matricyrptin
  • proteomics
  • remodeling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Lindsey, M. L., Iyer, R. P., Zamilpa, R., Yabluchanskiy, A., DeLeon-Pennell, K. Y., Hall, M. E., Kaplan, A., Zouein, F. A., Bratton, D., Flynn, E. R., Cannon, P. L., Tian, Y., Jin, Y. F., Lange, R. A., Tokmina-Roszyk, D., Fields, G. B., & De Castro Brás, L. E. (2015). A Novel Collagen Matricryptin Reduces Left Ventricular Dilation Post-Myocardial Infarction by Promoting Scar Formation and Angiogenesis. Journal of the American College of Cardiology, 66(12), 1364-1374. https://doi.org/10.1016/j.jacc.2015.07.035