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

Purpose: Low molecular weight carbonyl compounds, such as the alpha-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 PDGFR beta-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 PDGFR beta and in part from altered PDGF-BB binding to PDGFR beta. Concomitantly, the formation of AGE adducts (N-epsilon carboxymethyl-ly-sine and N-epsilon carboxyethyl-lysine) was observed on immunoprecipitated PDGFR beta. Arginine and aminoguanidine, used as carbonyl scavengers, reversed the inhibitory effect and the formation of AGE adducts on PDGFR beta. AGE-PDGFR beta adducts were also detected by anti-AGE antibodies in PDGFR beta 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 PDGFR beta that helps to reduce mesenchymal cell proliferation.