Abstract
Supplemental oxygen is frequently used together with mechanical ventilation to achieve sufficient blood oxygenation. Despite the undoubted benefits, it is vigorously debated whether too much oxygen can also have unpredicted side-effects. Uncertainty is also due to the fact that the molecular mechanisms are still insufficiently understood. The lung endothelium is covered with an exceptionally broad glycocalyx, carrying N- and O-glycans, proteoglycans, glycolipids and glycosaminoglycans. Glycan structures are not genetically determined but depend on the metabolic state and the expression level and activity of biosynthetic and glycan remodeling enzymes, which can be influenced by oxygen and the redox status of the cell. Altered glycan structures can affect cell interactions and signaling. In this study, we investigated the effect of different oxygen conditions on aspects of the glycobiology of the pulmonary endothelium with an emphasis on N-glycans and terminal sialylation using an in vitro cell culture system. We combined a proteomic approach with N-glycan structure analysis by LC-MS, qRT-PCR, sialic acid analysis and lectin binding to show that constant and intermittent hyperoxia induced time dependent changes in global and surface glycosylation. An siRNA approach identified St6gal1 as being primarily responsible for the early transient increase of α2-6 sialylated structures in response to hyperoxia.
Highlights
Introduction published maps and institutional affilA primary function of the pulmonary endothelium is the formation of a barrier between the blood and the interstitium providing controlled extravasation of fluid, proteins and cells
We aimed to investigate whether altered partial pressures of oxygen, as they are encountered directly by the pulmonary endothelium in vivo, have an influence on proteins involved in the synthesis and modification of cellular glycan structures in pulmonary endothelial cell cultures
Persistent hyperoxia induces a short-term disruption of homeostasis in N-glycosylation of lung endothelial cells, which occurs as an increase in the general degree of total N-glycosylation and especially complex sialylated N-glycans
Summary
A primary function of the pulmonary endothelium is the formation of a barrier between the blood and the interstitium providing controlled extravasation of fluid, proteins and cells. The pulmonary endothelium is a single cell layer of specialized cells with a unique metabolism, which are connected by tight and adherens junctions to form this barrier [2]. The luminal surface of endothelial cells is covered with a glycan-rich layer, generally termed glycocalyx, which is exceptionally thick (approximately 2 μm) in the lung microvasculature and is even observed with lung microvascular endothelial cells in culture [3]. The glycocalyx comprises glycans from glycoproteins, proteoglycans (syndecans and glypicans) and glycosaminoglycans (heparan sulfate and hyaluronic acid) with a high density of iations
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