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

作者：Lindsey Merry L; Iyer Rugmani Padmanabhan; Zamilpa Rogelio; Yabluchanskiy Andriy; DeLeon Pennell Kristine Y; Hall Michael E; Kaplan Abdullah; Zouein Fouad A; Bratton Dustin; Flynn Elizabeth R; Cannon Presley L; Tian Yuan; Jin Yu Fang; Lange Richard A; Tokmina Roszyk Dorota; Fields Gregg B; Bras Lisandra E de Castro^*

来源：Journal of the American College of Cardiology, 2015, 66(12): 1364-1374.

DOI：10.1016/j.jacc.2015.07.035

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

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 Ia1 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 Ia1 matricryptin p1158/59 facilitates LV remodeling post-MI by regulating scar formation through targeted ECM generation and stimulation of angiogenesis.

• 出版日期2015-9-22