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Methylglyoxal induces advanced glycation end product (AGEs) formation and dysfunction of PDGF receptor-ß: implications for diabetic atherosclerosis

Anne-Valerie Cantero^*,1, Manuel Portero-Otín^,1, Victòria Ayala, Nathalie Auge^*, Marie Sanson^*, Meyer Elbaz^*, Jean-Claude Thiers^*, Reinald Pamplona, Robert Salvayre^*,2 and Anne Nègre-Salvayre^*,2

^* Inserm U-466 and Biochemistry Department, IFR 31, CHU Rangueil, University Paul Sabatier, Toulouse, France; and

Metabolic Pathophysiology Research Group, Department of Basic Medical Sciences, University of Lleida, Spain

²Correspondence: INSERM U466, IFR 31, CHU Rangueil, Toulouse 31059 Cedex 9, TSA 50032, France. E-mail: anesalv{at}toulouse.inserm.fr or salvayre{at}toulouse.inserm.fr

Purpose: Low molecular weight carbonyl compounds, such as the -ketoaldehydes methylglyoxal (MGO) and glyoxal (GO), are formed under hyperglycemic conditions and behave as advanced glycation end product (AGE) precursors. They form adducts on proteins, thereby inducing cellular dysfunctions involved in chronic complications of diabetes. Methods and main findings: Nontoxic concentrations of GO or MGO altered the PDGF-induced PDGFRß-phosphorylation, ERK1/2-activation, and nuclear translocation, and the subsequent proliferation of mesenchymal cells (smooth muscle cells and skin fibroblasts). This resulted mainly from inhibition of the intrinsic tyrosine kinase of PDGFRß and in part from altered PDGF-BB binding to PDGFRß. Concomitantly, the formation of AGE adducts (Ncarboxymethyl-lysine and Ncarboxyethyl-lysine) was observed on immunoprecipitated PDGFRß. Arginine and aminoguanidine, used as carbonyl scavengers, reversed the inhibitory effect and the formation of AGE adducts on PDGFRß. AGE-PDGFRß adducts were also detected by anti-AGE antibodies in PDGFRß immunopurified from aortas of diabetic (streptozotocin-treated) compared to nondiabetic apolipoprotein E-null mice. Mass spectrometry analysis of aortas demonstrated increased AGE formation in diabetic specimens. Conclusions: these data indicate that MGO and GO induce desensitization of PDGFRß that helps to reduce mesenchymal cell proliferation.—Cantero, A.-V., Portero-Otín, M., Ayala, V., Auge, N., Sanson, M., Elbaz, M., Thiers, J-C., Pamplona, R., Salvayre, R., Nègre-Salvayre, A. Methylglyoxal induces advanced glycation end product (AGEs) formation and dysfunction of PDGF receptor-ß: implications for diabetic atherosclerosis.

Key Words: oxidative stress • growth arrest • MGO • wound healing • apoptosis