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J. Biol. Chem. 287 (14): 11363-11373

© 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Background: Heparan sulfates (HS) are important cell behavior regulators.

Results: With age, HS structural changes affect myocardial growth factor functionalities.

Conclusion: This reveals the importance of HS on the control of essential tissue repair effectors during aging.

Significance: Changes in cardiac HS may alter tissue homeostasis and impair heart function. This might also limit the success of protein therapies and implantation of therapeutic cells.

Age-related Changes in Rat Myocardium Involve Altered Capacities of Glycosaminoglycans to Potentiate Growth Factor Functions and Heparan Sulfate-altered Sulfation*Formula

Minh Bao Huynh{ddagger}1, Christophe Morin{ddagger}, Gilles Carpentier{ddagger}, Stephanie Garcia-Filipe{ddagger}, Sofia Talhas-Perret{ddagger}, Véronique Barbier-Chassefière{ddagger}, Toin H. van Kuppevelt§, Isabelle Martelly{ddagger}, Patricia Albanese{ddagger}, , and Dulce Papy-Garcia{ddagger}2

From the {ddagger}Laboratoire Croissance, Reparation et Regeneration Tissulaires EAC/CNRS-7149, Université Paris Est Créteil, 94010 Créteil, France and
the §Department of Matrix Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HC Nijmegen, The Netherlands.

ABSTRACT Back to Top

Abstract: Glycosaminoglycans (GAGs) are essential components of the extracellular matrix, the natural environment from which cell behavior is regulated by a number or tissue homeostasis guarantors including growth factors. Because most heparin-binding growth factor activities are regulated by GAGs, structural and functional alterations of these polysaccharides may consequently affect the integrity of tissues during critical physiological and pathological processes. Here, we investigated whether the aging process can induce changes in the myocardial GAG composition in rats and whether these changes can affect the activities of particular heparin-binding growth factors known to sustain cardiac tissue integrity. Our results showed an age-dependent increase of GAG levels in the left ventricle. Biochemical and immunohistological studies pointed out heparan sulfates (HS) as the GAG species that increased with age. ELISA-based competition assays showed altered capacities of the aged myocardial GAGs to bind FGF-1, FGF-2, and VEGF but not HB EGF. Mitogenic assays in cultured cells showed an age-dependent decrease of the elderly GAG capacities to potentiate FGF-2 whereas the potentiating effect on VEGF165 was increased, as confirmed by augmented angiogenic cell proliferation in Matrigel plugs. Moreover, HS disaccharide analysis showed considerably altered 6-O-sulfation with modest changes in N- and 2-O-sulfations. Together, these findings suggest a physiological significance of HS structural and functional alterations during aging. This can be associated with an age-dependent decline of the extracellular matrix capacity to efficiently modulate not only the activity of resident or therapeutic growth factors but also the homing of resident or therapeutic cells.

Key Words: Cardiac Muscle • Fibroblast Growth Factor (FGF) • Glycosaminoglycan • Heparan Sulfate • Vascular Endothelial Growth Factor (VEGF)

Received for publication December 20, 2011. Revision received January 17, 2012.


1 Supported by the French Ministry of Superior Education and Research.

2 To whom correspondence should be addressed: 61 avenue du Général de Gaulle, Créteil 94010 cedex, France. Tel.: 33-1451-77081; Fax: 33-1451-71816; E-mail: papy{at}

Myocardial Extracellular Matrix: An Ever-Changing and Diverse Entity.
M. Rienks, A.-P. Papageorgiou, N. G. Frangogiannis, and S. Heymans (2014)
Circ. Res. 114, 872-888
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