Sirtuin 1 reduces hyaluronan synthase 2 expression by inhibiting nuclear translocation of NF-?B and expression of the long-noncoding RNA HAS2?AS1
Sirtuin 1 reduces hyaluronan synthase 2 expression by inhibiting nuclear translocation of NF-?B and expression of the long-noncoding RNA HAS2?AS1
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DOI：
10.1074/jbc.ra119.011982
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发表时间：
2020-03-13
影响因子：
4.8
通讯作者：
Vigetti, Davide
中科院分区：
文献类型：
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作者：
Caon, Ilaria;Bartolini, Barbara;Vigetti, Davide
透明质酸 (HA) 是血管细胞外基质 (ECM) 中最常见的糖胺聚糖之一。血管壁内HA的异常积累与组织炎症有关，并且在大多数血管病理状况（例如动脉粥样硬化和再狭窄）中尤为突出。透明质酸合酶 2 (HAS2) 是参与 HA 合成的主要透明质酸合酶，使用胞质 UDP-葡萄糖醛酸和 UDP-GlcNAc 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比率，该酶将C6处的醇基氧化为COO？团体。在这里，我们发现 HAS2 的表达可以通过 Sirtuin 1 (SIRT1) 来调节，SIRT1 是细胞的主要代谢传感器，属于 NAD(+) 依赖性脱乙酰酶类。我们的结果揭示了以下内容。 1) 用 SIRT1 激活剂（SRT1720 和白藜芦醇）处理人主动脉平滑肌细胞 (AoSMC) 可抑制 HAS2 表达和细胞周 HA 涂层的积累。 2）肿瘤坏死因子？ (TNF?) 诱导 HA 介导的单核细胞粘附和 AoSMC 迁移，而 SIRT1 激活通过降低 HA 介导的运动受体、RHAMM 和 HA 结合蛋白 TNF 刺激基因 6 蛋白 (TSG6) 的表达水平来阻止免疫细胞募集和细胞运动。 3) SIRT1激活阻止了NF-κB (p65)的核转位，这反过来又降低了HAS2?AS1的水平，HAS2?AS1是一种表观遗传控制HAS2 mRNA表达的长非编码RNA。总之，我们证明 AoSMC 的 HAS2 表达和 HA 积累均受到代谢传感器 SIRT1 的下调。
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 ? (TNF?) 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-?B (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.