Changes in extracellular matrix (ECM) composition occur with injury, disease, or aging and may result in altered tissue homeostasis and integrity. Heparan sulfates (HS), chondroitin sulfates, and hyaluronans are subfamilies of long polysaccharides collectively known as glycosaminoglycans (GAGs) that can affect cellular signaling pathways by interacting with cytokines and growth factors or by acting as ligands for cell-surface receptors. Huynh et al. found that the overall abundance of sulfated GAGs in the left ventricular myocardium of rats increased with age (comparing 4-, 12-, 18-, and 24-month-old animals). Further analysis indicated that an increase in HS accounted for this increase in total GAGs. GAGs from young (4-month-old) and aged (24-month-old) rats also differed qualitatively, because GAGs extracted from aged myocardium exhibited increased affinity for a heparin-binding isoform of vascular endothelial growth factor (VEGF165) and decreased affinity for fibroblast growth factors 1 and 2 (FGF1 and FGF2), and HS derived from aged hearts showed decreased affinity for FGF2. To determine the effects of GAGs derived from young and aged hearts on cellular responses to these ligands, the authors used the BaF32 lymphoblastoid cell line, which lacks cell-surface HS, expresses transgenically encoded FGF receptor 1 (FGFR1), and proliferates in response to FGF2 only in the presence of exogenously supplied GAGs or heparin. In this assay, aged heart–derived GAGs potentiated FGF2-induced proliferation less than did GAGs derived from young hearts. In contrast, GAGs derived from aged hearts were better at promoting VEGF165-induced proliferation of human umbilical vein endothelial cells (HUVECs) than were GAGs from young hearts. HS show great variety in the sulfation of their disaccharide building blocks, and the authors noted that the sulfation patterns differed between young and aged HS, suggesting that the biosynthesis of HS changed as the animals aged. It is therefore possible that age-related changes in ECM composition could affect the ability of tissues like the myocardium to maintain integrity, regenerate, or recover from stress, potentially contributing to the impairment of heart function in elderly humans.
M. B. Huynh, C. Morin, G. Carpentier, S. Garcia-Filipe, S. Talhas-Perret, V. Barbier-Chassefière, T. H. van Kuppevelt, I. Martelly, P. Albanese, D. Papy-Garcia, Age-related changes in rat myocardium involve altered capacities of glycosaminoglycans to potentiate growth factor functions and heparan sulfate-altered sulfation. J. Biol. Chem. 287, 11363–11373 (2012). [Abstract] [Full Text]