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 HAS enzyme involved in HA synthesis and uses cytosolic UDP-glucuronic acid and UDP-N-acetyl glucosamine 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 that 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 AoSMCs 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-kB (p65), which, in turn, reduced the levels of HAS2-AS1, a long-non coding 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.

中文翻译：

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Sirtuin 1通过抑制NF-kB的核易位和长非编码RNA HAS2-AS1的表达来降低透明质酸合酶2的表达。

透明质酸（HA）是血管细胞外基质（ECM）中最普遍的糖胺聚糖之一。HA在血管壁内的异常积累与组织炎症有关，并且在大多数血管病理状况如动脉粥样硬化和再狭窄中很明显。透明质酸合酶2（HAS2）是参与HA合成的主要HAS酶，并使用胞质UDP-葡萄糖醛酸和UDP-N-乙酰氨基葡萄糖作为底物。UDP-葡萄糖醛酸的合成可以通过UDP-葡萄糖脱氢酶改变NAD +：NADH的比例，该酶将C6处的醇基氧化为COO-基团。在这里，我们表明，HAS2表达可以被Sirtuin 1（SIRT1）调节，该蛋白是细胞的主要代谢传感器，属于NAD +依赖性脱乙酰基酶。我们的结果表明，1）用SIRT1激活剂（SRT1720和白藜芦醇）处理人的主动脉平滑肌细胞（AoSMCs）既能抑制HAS2的表达，又能抑制细胞周围HA涂层的积累。2）肿瘤坏死因子α（TNFα）诱导HA介导的单核细胞粘附和AoSMCs迁移，而SIRT1激活通过降低HA介导的运动，RHAMM和HA结合的受体的表达水平来阻止免疫细胞募集和细胞运动TNF刺激的基因6蛋白（TSG6）。3）SIRT1激活阻止了NF-kB（p65）的核易位，继而降低了HAS2-AS1的水平，HAS2-AS1是一种长非编码RNA，通过表观遗传控制HAS2 mRNA的表达。总之，我们证明代谢传感器SIRT1会下调AoSMCs的HAS2表达和HA积累。