Hypoxia modifies the effect of PDGF on glycosaminoglycan synthesis by primary human lung cells.
Hypoxia, a consequence of interstitial lung diseases, may lead to secondary pulmonary hypertension and pulmonary vascular remodeling. Hypoxia induces activation and proliferation of lung cells and enhances the deposition of extracellular matrix including glycosaminoglycans (GAGs). To elucidate the cell biological mechanisms underlying the development of secondary pulmonary hypertension, we studied the effect of hypoxia on GAG synthesis by human lung cells. GAG synthesis was measured by incorporation of [(3)H]glucosamine; GAGs were isolated, purified, and characterized with GAG-degrading enzymes. Fibroblasts and vascular smooth muscle cells (VSMCs) synthesized hyaluronic acid, heparan sulfate, and chondroitin sulfates, whereas dermatan sulfate was found only in fibroblasts. Hypoxia did not influence the size or charge of the individual GAGs. However, hypoxia inhibited platelet-derived growth factor-induced [(3)H]glucosamine incorporation in secreted GAGs, especially hyaluronic acid, in VSMCs. In contrast, it stimulated GAG secretion, specifically heparan sulfate, by fibroblasts. Our results indicate that hypoxia induces modifications in GAG synthesis by human lung VSMCs and fibroblasts that may be correlated to pathophysiological manifestations in lung diseases causing hypoxia.
Papakonstantinou
E
E
Department of Pharmacology, School of Medicine, Aristotle University, 54006 Thessaloniki, Greece.
Karakiulakis
G
G
Tamm
M
M
Perruchoud
A P
AP
Roth
M
M
D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D002810:Chondroitinases and Chondroitin Lyases / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005944:Glucosamine / Q000378:metabolism; D006025:Glycosaminoglycans / Q000096:biosynthesis*; D006026:Glycoside Hydrolases; D019763:Heparin Lyase / Q000494:pharmacology; D006801:Humans; D006820:Hyaluronic Acid / Q000096:biosynthesis; D006821:Hyaluronoglucosaminidase / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011133:Polysaccharide-Lyases / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001616:beta-Galactosidase / Q000494:pharmacology
D006025:Glycosaminoglycans; D010982:Platelet-Derived Growth Factor; D006820:Hyaluronic Acid; D006026:Glycoside Hydrolases; C026093:keratan-sulfate endo-1,4-beta-galactosidase; D001616:beta-Galactosidase; D006821:Hyaluronoglucosaminidase; D002810:Chondroitinases and Chondroitin Lyases; D011133:Polysaccharide-Lyases; D019763:Heparin Lyase; C021349:heparitinsulfate lyase; D005944:Glucosamine