Pyridoxamine prevents increased atherosclerosis by intermittent methylglyoxal spikes in the aortic arches of ApoE-/- mice

Nordin M.J. Hanssen, Chris Tikellis, Raelene J. Pickering, Dragana Dragoljevic, Man Kit Sam Lee, Tomasz Block, Jean LJM Scheijen, Kristiaan Wouters, Toshio Miyata, Mark E. Cooper, Andrew J. Murphy, Merlin C. Thomas, Casper G. Schalkwijk

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2 Citations (Scopus)

Abstract

Methylglyoxal (MGO) is a reactive glucose metabolite linked to diabetic cardiovascular disease (CVD). MGO levels surge during intermittent hyperglycemia. We hypothesize that these MGO spikes contribute to atherosclerosis, and that pyridoxamine as a MGO quencher prevents this injury. To study this, we intravenously injected normoglycemic 8-week old male C57Bl6 ApoE-/- mice with normal saline (NS, n = 10) or 25 µg MGO for 10 consecutive weeks (MGOiv, n = 11) with or without 1 g/L pyridoxamine (MGOiv+PD, n = 11) in the drinking water. We measured circulating immune cells by flow cytometry. We quantified aortic arch lesion area in aortic roots after Sudan-black staining. We quantified the expression of inflammatory genes in the aorta by qPCR. Intermittent MGO spikes weekly increased atherosclerotic burden in the arch 1.8-fold (NS: 0.9 ± 0.1 vs 1.6 ± 0.2 %), and this was prevented by pyridoxamine (0.8 ± 0.1 %). MGOiv spikes increased circulating neutrophils and monocytes (2-fold relative to NS) and the expression of ICAM (3-fold), RAGE (5-fold), S100A9 (2-fold) and MCP1 (2-fold). All these changes were attenuated by pyridoxamine. This study suggests that MGO spikes damages the vasculature independently of plasma glucose levels.

Original languageEnglish
Article number114211
Number of pages9
JournalBiomedicine & Pharmacotherapy
Volume158
DOIs
Publication statusPublished - Feb 2023

Keywords

  • Atherosclerosis
  • Diabetes
  • Dicarbonyl stress
  • Methylglyoxal
  • Pyridoxamine

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