Methylglyoxal-Induced Endothelial Cell Loss and Inflammation Contribute to the Development of Diabetic Cardiomyopathy

Diabetes. 2016 Jun;65(6):1699-713. doi: 10.2337/db15-0568. Epub 2016 Mar 8.

Abstract

The mechanisms for the development of diabetic cardiomyopathy remain largely unknown. Methylglyoxal (MG) can accumulate and promote inflammation and vascular damage in diabetes. We examined if overexpression of the MG-metabolizing enzyme glyoxalase 1 (GLO1) in macrophages and the vasculature could reduce MG-induced inflammation and prevent ventricular dysfunction in diabetes. Hyperglycemia increased circulating inflammatory markers in wild-type (WT) but not in GLO1-overexpressing mice. Endothelial cell number was reduced in WT-diabetic hearts compared with nondiabetic controls, whereas GLO1 overexpression preserved capillary density. Neuregulin production, endothelial nitric oxide synthase dimerization, and Bcl-2 expression in endothelial cells was maintained in the hearts of GLO1-diabetic mice and corresponded to less myocardial cell death compared with the WT-diabetic group. Lower receptor for advanced glycation end products and tumor necrosis factor-α (TNF-α) levels were also observed in GLO1-diabetic versus WT-diabetic mice. Over a period of 8 weeks of hyperglycemia, GLO1 overexpression delayed and limited the loss of cardiac function. In vitro, MG and TNF-α were shown to synergize in promoting endothelial cell death, which was associated with increased angiopoietin 2 expression and reduced Bcl-2 expression. These results suggest that MG in diabetes increases inflammation, leading to endothelial cell loss. This contributes to the development of diabetic cardiomyopathy and identifies MG-induced endothelial inflammation as a target for therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-2 / metabolism
  • Animals
  • Case-Control Studies
  • Cell Death
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Cardiomyopathies / etiology*
  • Endothelial Cells / metabolism*
  • Genes, bcl-2
  • Glycation End Products, Advanced / metabolism
  • Lactoylglutathione Lyase / metabolism*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myocarditis / metabolism
  • Myocardium / metabolism
  • Pyruvaldehyde / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Angiopoietin-2
  • Glycation End Products, Advanced
  • Tumor Necrosis Factor-alpha
  • Pyruvaldehyde
  • Lactoylglutathione Lyase