Methylglyoxal-derived advanced glycation end products contribute to negative cardiac remodeling and dysfunction post-myocardial infarction
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Advanced glycation end-products (AGEs) have been associated with poorer outcomes after myocardial infarction (MI), and linked with heart failure. Methylglyoxal (MG) is considered the most important AGE precursor, but its role in MI is unknown. In this study, we investigated the involvement of MG-derived AGEs (MG-AGEs) in MI using transgenic mice that over-express the MG-metabolizing enzyme glyoxalase-1 (GLO1). MI was induced in GLO1 mice and wild-type (WT) littermates. At 6 h post-MI, mass spectrometry revealed that MG-H1 (a principal MG-AGE) was increased in the hearts of WT mice, and immunohistochemistry demonstrated that this persisted for 4 weeks. GLO1 over-expression reduced MG-AGE levels at 6 h and 4 weeks, and GLO1 mice exhibited superior cardiac function at 4 weeks post-MI compared to WT mice. Immunohistochemistry revealed greater vascular density and reduced cardiomyocyte apoptosis in GLO1 vs. WT mice. The recruitment of c-kit+ cells and their incorporation into the vasculature (c-kit+CD31+ cells) was higher in the infarcted myocardium of GLO1 mice. MG-AGEs appeared to accumulate in type I collagen surrounding arterioles, prompting investigation in vitro. In culture, the interaction of angiogenic bone marrow cells with MG-modified collagen resulted in reduced cell adhesion, increased susceptibility to apoptosis, fewer progenitor cells, and reduced angiogenic potential. This study reveals that MG-AGEs are produced post-MI and identifies a causative role for their accumulation in the cellular changes, adverse remodeling and functional loss of the heart after MI. MG may represent a novel target for preventing damage and improving function of the infarcted heart.
KeywordsAdvanced glycation end-products Bone marrow cells Extracellular matrix Glyoxalase-1 Methylglyoxal Myocardial infarction
The authors would like to thank Rick Seymour and Suzanne Crowe (University of Ottawa Heart Institute) for technical support. This work was supported by operating Grants from the Heart and Stroke Foundation of Canada (HSFC; GIA-000225), and the Canadian Institutes of Health Research (CIHR; FRN 125678). Nick Blackburn was supported by a University of Ottawa Faculty of Medicine Endowed Fund for Cardiac Research and the UOHI Foundation; Branka Vulesevic by a Canadian Graduate Scholarship from the CIHR; and Brian McNeill by a Research Fellowship Award from the HSFC.
Compliance with ethical standards
Conflict of interest
PJB has a financial interest in PreventAGE Healthcare, where the mass spectrometry of MG-AGEs was performed. The authors declare no other potential conflicts of interest.
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