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

Abstract

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 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.

• Authors: Anne-Valerie Cantero, Manuel Portero-Otín, Victòria Ayala, Nathalie Auge, Marie Sanson, Meyer Elbaz, Jean-Claude Thiers, Reinald Pamplona, Robert Salvayre, Anne Nègre-Salvayre
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 21 Issue 12 Pg. 3096-106 (Oct 2007) ISSN: 1530-6860 [Electronic] United States
• PMID: 17504976 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Glycation End Products, Advanced
• Guanidines
• Platelet-Derived Growth Factor
• Proto-Oncogene Proteins c-sis
• Becaplermin
• Glyoxal
• Pyruvaldehyde
• Arginine
• Protein-Tyrosine Kinases
• Receptor, Platelet-Derived Growth Factor beta
• pimagedine

Topics

• Animals
• Aorta (cytology, metabolism, pathology)
• Apolipoproteins E (genetics, metabolism)
• Arginine (metabolism)
• Atherosclerosis (etiology, metabolism, pathology)
• Becaplermin
• Cell Movement (physiology)
• Cell Proliferation
• Cells, Cultured
• Diabetes Complications
• Diabetes Mellitus, Experimental
• Glycation End Products, Advanced (metabolism)
• Glyoxal (metabolism)
• Guanidines (metabolism)
• Humans
• Mesoderm (cytology, metabolism)
• Mice
• Mice, Knockout
• Myocytes, Smooth Muscle (cytology, metabolism)
• Platelet-Derived Growth Factor (metabolism)
• Protein-Tyrosine Kinases (metabolism)
• Proto-Oncogene Proteins c-sis
• Pyruvaldehyde (metabolism)
• Rabbits
• Receptor, Platelet-Derived Growth Factor beta (genetics, metabolism)