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


RESULTS
Nontoxic concentrations of GO or MGO altered the PDGF-induced PDGFRbeta-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 PDGFRbeta and in part from altered PDGF-BB binding to PDGFRbeta. Concomitantly, the formation of AGE adducts (N(epsilon)carboxymethyl-lysine and N(epsilon)carboxyethyl-lysine) was observed on immunoprecipitated PDGFRbeta. Arginine and aminoguanidine, used as carbonyl scavengers, reversed the inhibitory effect and the formation of AGE adducts on PDGFRbeta. AGE-PDGFRbeta adducts were also detected by anti-AGE antibodies in PDGFRbeta 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 PDGFRbeta that helps to reduce mesenchymal cell proliferation.
Cantero
Anne-Valerie
AV
Inserm U-466 and Biochemistry Department, IFR 31, CHU Rangueil, University Paul Sabatier, Toulouse, France.
Portero-Otín
Manuel
M
Ayala
Victòria
V
Auge
Nathalie
N
Sanson
Marie
M
Elbaz
Meyer
M
Thiers
Jean-Claude
JC
Pamplona
Reinald
R
Salvayre
Robert
R
Nègre-Salvayre
Anne
A
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001120:Arginine / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000077214:Becaplermin; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D048909:Diabetes Complications; D003921:Diabetes Mellitus, Experimental; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006037:Glyoxal / Q000378:metabolism; D006146:Guanidines / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D011765:Pyruvaldehyde / Q000378:metabolism*; D011817:Rabbits; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D001057:Apolipoproteins E; D017127:Glycation End Products, Advanced; D006146:Guanidines; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D006037:Glyoxal; D011765:Pyruvaldehyde; D001120:Arginine; D011505:Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; C004479:pimagedine