Abstract 14257: Glyoxalase-1 Over-expression Preserves Cardiac Function Post-MI by Enhancing Vascularity and Reducing AGE Accumulation and Cardiomyocyte Apoptosis
Background: Advanced glycation end product (AGE) formation is thought to contribute to disease pathogenesis and methylglyoxal (MG) is a major AGE precursor. Myocardial infarction (MI) stimulates the rapid production of MG-AGEs, but the associated effects are poorly defined. Therefore, we explored the role of MG-derived AGEs in MI using a transgenic mouse model that over-expresses glyoxalase-1 (GLO1), a MG metabolizing enzyme.
Methods/Results: MI was induced in GLO1 mice, and their wild-type (WT) littermates. By 2 days post-MI GLO1 mice had reduced MG-AGE accumulation (by 26%, p=0.04) in the infarct compared to WT, and at 4 weeks post-MI also had smaller infarct size (41.5±2.2% vs. 57.3±7.1%, p=0.05). By echocardiography, cardiac function (%LVEF) at 4wk was observed to be greater in GLO1 mice than in WT (46.0±3.3% vs. 33.9±1.8%, p=0.008). Immunohistochemistry of tissue sections collected at 4 weeks post-MI revealed greater arteriole (by 127%) and capillary density (by 130%) in GLO1 vs. WT mice (p=0.006 and p=0.03, respectively). The number of apoptotic cardiomyocytes (active caspase-3+) was reduced in GLO1 mice compared to WT (20±2% vs. 28±3% per FOV, p=0.05). Collagen is a major target for glycation, and also an important mediator of cell fate and survival. Thus, we explored the effect of MG-modified collagen on circulating angiogenic cells (CACs), which are known to participate in post-MI neovascularization. In vitro, CACs cultured on MG-modified collagen vs. unmodified collagen resulted in: 1) reduced CAC adhesion (p=0.005); 2) increased apoptosis in hypoxic conditions (p=0.05); 3) fewer pro-angiogenic CD34+ and CD133+ progenitors (p≤0.005); and 4) a decreased capacity to promote neovascularization measured by network length in a CAC-HUVEC angiogenesis assay (p=0.005).
Conclusion: This is the first study reporting a significant role for MG in the pathogenesis of MI, which can be reduced by over-expression of GLO1. We also show that MG-mediated collagen modification may contribute to the impaired endogenous repair response of CACs. Therefore, intervening on MG production and restoring ECM signaling in the MI heart may improve endogenous repair, and make the cardiac environment more amenable to therapy.
- © 2013 by American Heart Association, Inc.