Abstract 19443: Methylglyoxal Impairs Neovascularization Post-MI Through ECM Modification
Introduction: Methylglyoxal (MG) is the most important Advanced Glycation End-product (AGE) precursor and the extracellular matrix (ECM) is a major target for glycation. AGEs have been implicated in heart disease, but the role of MG in myocardial infarction (MI) remains to be elucidated. We hypothesized that MG contributes to cardiac dysfunction and remodeling post-MI and that the modification of ECM proteins impairs the neovascularization response.
Methods/Results: Glyoxalase-1 (GLO1; a MG metabolizing enzyme) was over-expressed in the vasculature of mice and experimental MI was induced in GLO1 transgenic mice and their WT littermates. Mice were followed for 28 days. In vitro, laminin, fibronectin, and collagens were coated onto tissue culture plates and treated with MG for 24h, and the adhesion and viability of endothelial cells (ECs) and bone marrow cells (BMCs) was assessed. Finally, the effect of MG on the ability of ECMatrix to promote angiogenesis in vitro was evaluated. Mass spectrometry revealed that MI stimulated the production of MG at 6h, which was mitigated by GLO1 over-expression (p=0.007 for GLO1 vs. WT mice). At 4wk post-MI, echocardiography revealed superior LVEF in GLO1 mice (46.0±3.3%) compared to WT (33.9±1.8%, p=0.008). GLO1 mice also had smaller scar size (41.5±2.2%) vs. WT (57.3±7.1%; p=0.04). Immunohistology showed less MG-AGE accumulation in the ECM of GLO1 mice, and greater arteriole (p=0.006) and capillary (p=0.03) densities compared to WT. In vitro, western blot showed that laminin, and collagens I, III, and IV are modified by 1 and 10 mM MG, whereas fibronectin was not. EC adhesion was reduced on MG-modified laminin, and collagens III and IV at 1 and/or 4 hours compared to controls (p<0.05). For BMCs, culture on MG-collagen I: 1) reduced adhesion; 2) increased apoptosis; and 3) limited the ability of the cells to promote angiogenesis. MG modification of the commercial ECMatrix resulted in decreased capillary-like structure formation from seeded ECs by 35±5% (p<0.05).
Conclusion: This study confirms that MI stimulates the production of MG and that its accumulation is deleterious to post-MI repair. These detrimental effects are likely mediated, in part, through modification of the cardiac ECM and impaired neovascularization.
Author Disclosures: N.J. Blackburn: None. B. Nadlacki: None. B. Vulesevic: None. B. McNeill: None. A. Ostojic: None. D.J. Stewart: None. M. Brownlee: None. P.J. Beisswenger: None. R.W. Milne: None. E.J. Suuronen: None.
- © 2016 by American Heart Association, Inc.