title: Fibronectin glycation increases IGF-I induced proliferation of human aortic smooth muscle cells.
abstract: The advanced glycation end products, namely AGEs, contribute to long-termed complications of diabetes mellitus, including macroangiopathy, where smooth muscle cells (SMC) proliferation stimulated by platelet-derived growth factor (PDGF) isoforms and insulin-like growth factor-I (IGF-I) plays an important role. The objective of the present study was to investigate the effect of an AGE-modified extracellular matrix protein on IGF-I induced SMC proliferation and on the IGF-I-IGF binding protein 4 (IGFBP-4) axis under basal conditions and after stimulation with PDGF-BB. IGF-I resulted in significantly higher thymidine incorporation in SMC seeded on AGE-modified fibronectin (AGE-FN) in comparison to cells seeded on fibronectin (FN). This augmented proliferation could not be accounted for by increased expression of IGF-IR, by decreased secretion of IGFBP-4, a binding protein that inhibits IGF-I mitogenic effects or by increased IGF-IR autophosphorylation. PDGF-BB did not modulate IGF-IR and IGFBP-4 mRNA expression in any of the substrata, however, this growth factor elicited opposite effects on the IGFBP-4 content in the conditioned media, increasing it in cells plated on FN and diminishing it in cells plated on AGE-FN. These findings suggest that one mechanism by which AGE-modified proteins is involved in the pathogenesis of diabetes-associated atherosclerosis might be by increasing SMC susceptibility to IGF-I mitogenic effects.
authors.affiliation: Laboratory for Clinical and Experimental Gastroenterology (LIM-07), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Av, Dr, Arnaldo, 455, Sala #4387, São Paulo, Brazil. dgiannella@lim07.fm.usp.br.
authors.forename: Maria Lúcia
authors.initials: ML
authors.lastname: Corrêa-Giannella
authors.forename: Maria Regina Andrade
authors.initials: MR
authors.lastname: de Azevedo
authors.forename: Derek
authors.initials: D
authors.lastname: Leroith
authors.forename: Daniel
authors.initials: D
authors.lastname: Giannella-Neto