Sirtuin 1 reduces hyaluronan synthase 2 expression by inhibiting nuclear translocation of NF-κB and expression of the long-noncoding RNA HAS2–AS1

Abstract

Hyaluronan (HA) is one of the most prevalent glycosaminoglycans of the vascular extracellular matrix (ECM). Abnormal HA accumulation within blood vessel walls is associated with tissue inflammation and is prominent in most vascular pathological conditions such as atherosclerosis and restenosis. Hyaluronan synthase 2 (HAS2) is the main hyaluronan synthase enzyme involved in HA synthesis and uses cytosolic UDP-glucuronic acid and UDP-GlcNAc as substrates. The synthesis of UDP-glucuronic acid can alter the NAD+/NADH ratio via the enzyme UDP-glucose dehydrogenase, which oxidizes the alcohol group at C6 to the COO− group. Here, we show that HAS2 expression can be modulated by sirtuin 1 (SIRT1), the master metabolic sensor of the cell, belonging to the class of NAD+-dependent deacetylases. Our results revealed the following. 1) Treatments of human aortic smooth muscle cells (AoSMCs) with SIRT1 activators (SRT1720 and resveratrol) inhibit both HAS2 expression and accumulation of pericellular HA coats. 2) Tumor necrosis factor α (TNFα) induced HA-mediated monocyte adhesion and AoSMC migration, whereas SIRT1 activation prevented immune cell recruitment and cell motility by reducing the expression levels of the receptor for HA-mediated motility, RHAMM, and the HA-binding protein TNF-stimulated gene 6 protein (TSG6). 3) SIRT1 activation prevented nuclear translocation of NF-κB (p65), which, in turn, reduced the levels of HAS2–AS1, a long-noncoding RNA that epigenetically controls HAS2 mRNA expression. In conclusion, we demonstrate that both HAS2 expression and HA accumulation by AoSMCs are down-regulated by the metabolic sensor SIRT1.

Elucidating the Inhibitory Effect of Resveratrol and Its Structural Analogs on Selected Nucleotide-Related Enzymes

“…However, elucidating the mechanisms will still assist us in understanding how natural products interact with our proteome and how to enhance our health with natural products. Previous studies [ 51 , 52 , 53 , 54 , 55 , 56 ] and our results have demonstrated that resveratrol does interfere with the activities and alter the behavior of many proteins. It was proposed that the conventional one-drug-one-target paradigm cannot accurately describe the drug actions [ 57 ].…”

Cell Energy Metabolism and Hyaluronan Synthesis

“…The combined treatment with tumor necrosis factor α (TNFα) and SIRT1 activators inhibited AoSMCs migration and immune cells adhesion to the HA-rich ECM. From a mechanistic point of view, we demonstrated that the activation of SIRT1 prevented NF-kB/p65 nuclear translocation and decreased the levels of HAS2-AS1, which in turn regulates HAS2 43 (Fig. 3).…”

“…1). As HA deposition is mainly due to HAS2, 43 the study of its regulation is fundamental to understand HA biology. HAS2 displays a multistep regulation that involves the action of different growth factors and cytokines.…”

Integration of Sugar Metabolism and Proteoglycan Synthesis by UDP-glucose Dehydrogenase

“…20,21 Since high levels of UGDH activity have the potential to impact dynamic flux of NAD + /NADH ratios, it is also relevant to consider that UGDH impacts may be partially achieved through processes involving these redox cofactors. This is underscored by a recent report linking activation of the NAD + -dependent deacetylase, SIRT1, to the suppression of HA production via the transcriptional regulation of HAS2 (Caon et al 56 and reviewed in Caon et al 57 ).…”