Suppression of glycation stress via proteoglycan synthesis

<p>Proteoglycans (PGs) have sugar chains consisting of amino sugars and uronic acids repeated on a tetrasaccharide linker of xylose, galactose, galactose, and glucuronic acid attached to specific serine residue on the protein. Owing to these features, PGs are high-cost molecules requiring large amounts of amino acids, sugars, and ATP for synthesis. Nevertheless, PGs are synthesized in various species and continually secreted out of the cells. Therefore, it is expected that PGs synthesis has the physiological significance beyond organisms and molecular species.</p><p> Advanced glycation endproducts (AGEs) are produced by the non-enzymatic reaction of reducing sugars with amino groups of proteins. AGEs are known to increase reactive oxygen species (ROS) and cause cellular aging and vascular dysfunction. Although the above sugars involved in PGs synthesis are all reducing sugars, their reducing ability is lost during sugar chain elongation. For this reason, the reducing ability of PGs is much smaller than that of the source sugars. Therefore, we hypothesized that PGs synthesis would reduce the AGEs-mediated cellular injury by decreasing reactivity of reducing sugars and releasing PGs to the extracellular space. </p><p> Vascular endothelial cells were cultured in serum-free low D-glucose (5.55 mM) or D-glucose-addeed (40.55 mM) DMEM, after suppressing GlcAT-I involved in tetrasaccharide linker synthesis by RNA interference. After 48 h incubation, the amount of ROS was increased, and cell viability was decreased by GlcAT-I suppression. In addition, although intracellular AGEs and ROS levels were increased in the GlcAT-I-suppressed group under D-glucose supplemented condition, cell viability was not affected. These results suggest that PGs synthesis works as a defense system against AGEs formation and glycation stress accelerated by carbohydrate loading.</p>