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

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 We identified novel collagen-derived matricryptins generated post-MI that mediate remodeling of the left ventricle (LV). 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 versus 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.

The extracellular matrix in myocardial injury, repair, and remodeling

“…Low-molecular weight hyaluronan fragments exert potent proinflammatory actions in the infarcted region; impaired clearance of these fragments has been shown to prolong and accentuate proinflammatory signaling in leukocytes and vascular cells (42,43). Matrix fragments may also modulate fibroblast and vascular cell phenotype (44). Endostatin, a 20-kDa fragment of collagen XVIII, exerts potent angiostatic actions (45) and stimulates fibroblast proliferation (46).…”

Three-dimensional scaffolds of fetal decellularized hearts exhibit enhanced potential to support cardiac cells in comparison to the adult

“…Fetal bioscaffold leads to a decreased Cola1/Cola3 ratio characteristic of the developing heart and that has been suggested to contribute to the scarless phenotype seen in early stages of gestation [69]. Moreover, a decreased ratio of these two collagen forms has been shown to improve tissue remodeling in response to myocardial infarction [70]. In line with the induction of a more regenerative ECM, fetal matrices also enhanced the expression of paracrine factors by Sca-1 + cardiac progenitors, namely Tgfb1, Postn, Hbegf and Fn1.…”

Cerebral blood flow alteration following acute myocardial infarction in mice

“…Sixteen months old C57BL/6J male mice weighing 30–35 g underwent left anterior descending (LAD) coronary artery ligation surgery as previously described [28,29]. The age of experimental animals was chosen to represent translational power of our study and to mimic the average age of 50–55 years of MI incidence in humans [30].…”