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.
Highlights
Hyaluronan (HA) is one of the most prevalent glycosaminoglycans of the vascular extracellular matrix (ECM)
sirtuin 1 (SIRT1) reduces Hyaluronan synthase 2 (HAS2) expression via NF-B and HAS2–AS1 versely, its degradation is due to different hyaluronidases (HYAL1– 6) that work at acidic pH, and other related enzymes (i.e. TMEM2 and KIAA1199) that have an optimum pH around the physiological value [21, 22]
As HAS2 is a critical enzyme involved in atherosclerosis with vessel thickening and its transcription is regulated by NF-B [46], this study investigated whether HAS2 expression could be regulated by SIRT1 in human aortic smooth muscle cells and whether SIRT1 could control pro-atherogenic behavior of AoSMCs after TNF␣ proinflammatory treatments
Summary
AoSMCs generally produce high amounts of HA, which is the main component of vascular ECM, along with type I and III fibrillar collagen, elastin, and versican [47]. The treatment of SRT1720 or RESV together with TNF␣ restored HAS2 mRNA almost to control levels, indicating the ability of SIRT1 to modulate HAS2 expression and confirming the powerful anti-inflammatory effect of the compounds used. MRNA expression, whereas the simultaneous addition of 1 M SRT1720 or 100 M RESV significantly reduced the TSG6 messenger These results suggest that SIRT1 activators modulate the expression of the critical proteins involved in HA-mediated motility and inflammation, likely by formation of a monocyte adhesive HC–HA matrix. This combined treatment inhibited AoSMC migration (Fig. S6) and significantly decreased the expression of HAS2–AS1 and HAS2 compared with stimulation with TNF␣ alone (Fig. 7, C and D) These data confirm the critical role of SIRT1 activators in the regulation of a NF-B pathway and HAS2–AS1 expression
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