title: Fibrin(ogen) may be an important target for methylglyoxal-derived AGE modification in elastic arteries of humans.
abstract: Diabetes is associated with increased risk of cardiovascular disease. Advanced glycation end-products (AGEs) are considered to be a major pathogenic factor for diabetic vascular complications. The levels of AGEs are increased in diabetic patients. We have studied the presence of the major AGE methylglyoxal (MGO)-derived hydroimidazolone in human aorta and carotid arteries, using immunohistochemistry (IHC), western blotting and mass spectrometry. By IHC, MGO-derived modifications were detected mainly associated with cells in intimal thickenings and cells in microvessels in adventitia. In type V lesions MGO-derived AGE was also present, extracellular in the necrotic core and in cells at the border of the core. The highest degree of modification was probably associated with cell nuclei. By western blotting and mass spectrometry fibrin(ogen), the cytoskeleton-associated protein moesin and the nuclear proteins lamin A and C were identified as putative main targets for MGO-derived modification. LC-MS/MS studies of fibrin(ogen) modified in vitro with low concentrations of MGO identified the sites that were most prone to modification. These results indicate that AGE modifications occur preferentially on specific proteins. The modification of these proteins may play a role in vascular dysfunction and development of atherosclerosis in diabetes.
authors.affiliation: Department of Endocrinology – Section Hormone Laboratory, Oslo University Hospital, Norway. terjelu@medisin.uio.no
authors.forename: Terje
authors.initials: T
authors.lastname: Lund
authors.forename: Aud
authors.initials: A
authors.lastname: Svindland
authors.forename: Milaim
authors.initials: M
authors.lastname: Pepaj
authors.forename: Aase-Brith
authors.initials: AB
authors.lastname: Jensen
authors.forename: Jens P
authors.initials: JP
authors.lastname: Berg
authors.forename: Bente
authors.initials: B
authors.lastname: Kilhovd
authors.forename: Kristian F
authors.initials: KF
authors.lastname: Hanssen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D001011:Aorta / Q000737:chemistry* / Q000473:pathology; D015153:Blotting, Western; D017536:Carotid Artery, Common / Q000737:chemistry* / Q000473:pathology; D016022:Case-Control Studies; D002853:Chromatography, Liquid; D003925:Diabetic Angiopathies / Q000378:metabolism* / Q000473:pathology; D004548:Elasticity; D005260:Female; D005337:Fibrin / Q000032:analysis*; D005340:Fibrinogen / Q000032:analysis*; D017127:Glycation End Products, Advanced / Q000032:analysis*; D006801:Humans; D007093:Imidazoles / Q000032:analysis*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009336:Necrosis; D009664:Norway; D011499:Protein Processing, Post-Translational; D040901:Proteomics / Q000379:methods; D011765:Pyruvaldehyde / Q000032:analysis*; D053719:Tandem Mass Spectrometry
chemical_list: D017127:Glycation End Products, Advanced; D007093:Imidazoles; C117197:imidazolone; D011765:Pyruvaldehyde; D005337:Fibrin; D005340:Fibrinogen