title: Methylglyoxal-Induced Endothelial Cell Loss and Inflammation Contribute to the Development of Diabetic Cardiomyopathy.
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.
authors.affiliation: Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Branka
authors.initials: B
authors.lastname: Vulesevic
authors.affiliation: Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: McNeill
authors.affiliation: Diabetes Research Center, Departments of Internal Medicine and Pathology, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Giacco
authors.affiliation: Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Kay
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Nick J R
authors.initials: NJ
authors.lastname: Blackburn
authors.affiliation: Diabetes Research Center, Departments of Internal Medicine and Pathology, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Michael
authors.initials: M
authors.lastname: Brownlee
authors.affiliation: Diabetes and Atherosclerosis Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Ross W
authors.initials: RW
authors.lastname: Milne
authors.affiliation: Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada esuuronen@ottawaheart.ca.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Suuronen
mesh_terms: D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D016022:Case-Control Studies; D016923:Cell Death; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000209:etiology*; D042783:Endothelial Cells / Q000378:metabolism*; D019254:Genes, bcl-2; D017127:Glycation End Products, Advanced / Q000378:metabolism; D007791:Lactoylglutathione Lyase / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D011765:Pyruvaldehyde / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D042702:Angiopoietin-2; D017127:Glycation End Products, Advanced; D014409:Tumor Necrosis Factor-alpha; D011765:Pyruvaldehyde; D007791:Lactoylglutathione Lyase