Fibronectin glycation increases IGF-I induced proliferation of human aortic smooth muscle cells
1 Laboratory for Cellular and Molecular Endocrinology (LIM-25). Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455, Sala 4305, São Paulo, Brazil
2 Universidade Santo Amaro (UNISA), R. Enéas de Siqueira Neto, 340, São Paulo, Brazil
3 Division of Endocrinology and Diabetes, Department of Medicine, The Mount Sinai School of Medicine, 1 Gustave Levy Place, Box 1055, New York, USA
4 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
Diabetology & Metabolic Syndrome 2012, 4:19 doi:10.1186/1758-5996-4-19Published: 3 May 2012
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.