Inhibition of heparan sulfate synthesis by resveratrol in mucopolysaccharidosis type I and IIIB.

Abstract

Mucopolysaccharidoses (MPS) are a group of pediatric disorders that are distinguished based on a lysosomal enzyme deficit leading to accumulation of glycosaminoglycans (GAGs). One of the GAGs is heparan sulfate (HS) which accumulates in cells inside the body, but the most devastating symptoms are caused by its accumulation in the central nervous system. Resveratrol, a natural compound, reduces the HS accumulation in both MPS I and MPS IIIB. In this study, we investigated the effects of resveratrol on HS metabolism in cellular models of MPS I and MPS IIIB, with particular focus on its role in GAG synthesis and degradation. Resveratrol treatment resulted in a consistent reduction of HS levels in both models, as confirmed by dot-blot analysis. To determine the underlying mechanism, we analyzed the expression of genes involved in GAG biosynthesis and turnover, as well as heparanase activity. The expression of key genes involved in the early stages of GAG biosynthesis was modulated by resveratrol, suggesting inhibition of substrate production. In contrast, expressions of genes associated with extracellular matrix remodeling and GAG turnover were largely unchanged in MPS I and only partially affected in MPS IIIB. Analysis of the heparanase enzyme activity showed no significant changes in either model. Although alterations in extracellular heparanase activity were observed in MPS IIIB cells, these changes were normalized rather than enhanced by resveratrol treatment. Our results indicate that resveratrol reduces HS accumulation through inhibition of synthesis rather than induction of unspecific degradation by heparanase, supporting its potential as a substrate-reduction strategy in MPS.