Abstract 13353: Methylglyoxal Induces Stem Cell Dysfunction Through Impaired Matrix Interactions After Myocardial Infarction
Background: Advanced glycation end-products (AGEs) have been associated with poorer outcomes in heart failure (HF) after myocardial infarction (MI). The contribution of AGEs to post-MI injury has yet to be shown. Methylglyoxal (MG) is considered the most important AGE precursor. To elucidate the role of MG in post-MI repair, this study used a mouse model that over-expresses the MG-metabolizing enzyme glyoxalase-1 (GLO1).
Methods/Results: MI was induced in GLO1 over-expressing mice and their wild-type (WT) littermates. MI resulted in increased MG levels in hearts of both mouse groups. Left ventricular ejection fraction was superior in GLO1 mice (46.0±3.3%) compared to WT (33.9±1.8%, p=0.008) at 4 weeks post-MI. GLO1 mice also had smaller infarcts (41.5±2.2% vs. 57.3±7.1%, p=0.05) and improved chamber volumes. Immunohistochemistry at 4 weeks post-MI revealed greater arteriole (p=0.006) and capillary (p=0.03) density in GLO1 vs. WT mice, and an overall reduction in cardiomyocyte death through apoptosis (p=0.05) or necrosis (p<0.05). These improvements corresponded with a higher number of c-kit+ progenitor cells (p<0.05) and c-kit+CD31+ cells (p<0.05) in the infarcted myocardium. An increased abundance of c-kit+ progenitors was observed particularly surrounding vessels. By flow cytometry analysis of blood samples, superior release of bone marrow (BM) c-kit+ cells was excluded as a possible explanation for greater c-kit+ cell accumulation in the MI heart. Staining for MG-H1 (major MG-AGEs) showed increased collagen glycation in WT mouse hearts. Therefore, an in vitro model was used to assess the effect of glycated collagen on the function of BM derived progenitors. Overall, glycated collagen resulted in: 1) reduced adhesion; 2) increased susceptibility to apoptosis; 3) reduced proportion of CD34+ and CD133+ progenitors; and 4) limited ability of the cells to promote neovascularization.
Conclusion: This is the first study to confirm that MI stimulates the production of MG and that its accumulation is deleterious to post-MI repair. The detrimental effects of MG post-MI are mediated, in part, through collagen glycation and c-kit+ progenitor cell dysfunction. Intervening on MG could serve as a novel therapy for limiting the extent of damage post-MI.
Author Disclosures: N. Blackburn: None. B. Vulesevic: None. B. McNeill: None. A. Ostojic: None. R.W. Milne: None. E.J. Suuronen: None.
- © 2014 by American Heart Association, Inc.