SIRT1 reduces hyaluronan synthase 2 expression via NF-kB and HAS2-AS1

ILARIA CAON; ALANIZ LAURA; DAVIDE VIGETTI

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Lugar: Bethesda, Maryland; Año: 2020

0021-9258

Hyaluronan (HA) is one of the most represented glycosaminoglycan of vascular smooth muscle cell (SMC) extracellular matrix (ECM) which plays a critical role in the regulation of vascular wall properties. Interestingly, an abnormal accumulation of HA within vessel walls is often associated to tissue inflammation and it is peculiar of several vascular pathologic conditions, such as atherosclerosis and restenosis. Hyaluronan Synthase 2 (HAS2) is the main enzyme involved in HA synthesis by using cytosolic UDP glucuronic acid and UDP N-acetyl glucosamine as substrates. The synthesis of UDP glucuronic acid is able to alter NAD+:NADH ratio via the enzyme UDP glucose dehydrogenase that catalyzes the double oxidation of the alcoholic group of C6 to form 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 deacetilases. Our results demonstrate that the treatment with SIRT1 activators (SRT1720 and resveratrol) inhibits HAS2 expression and HA accumulation in human aortic smooth muscle cells (AoSMCs) pericellular coat. Moreover, TNFα induces HA-mediated monocyte adhesion and SIRT1 activator treatment prevents such immune cells recruitment reducing the proinflammatory response. At mechanistic level, we found that SIRT1 activation induces p65 deacetylation preventing its nuclear translocation, which in turn reduces the levels of HAS2-AS1, a long-non coding RNA that epigenetically controls HAS2 mRNA expression. In conclusion, we demonstrate for the first time that HAS2 expression and HA accumulation can be tightly regulated by SIRT1 which coordinates cell metabolism to several stress conditions and pathologies as well as aging.