title: Hyaluronan synthesis is inhibited by adenosine monophosphate-activated protein kinase through the regulation of HAS2 activity in human aortic smooth muscle cells.
abstract: Hyaluronan (HA) is an extracellular matrix glycosaminoglycan (GAG) involved in cell motility, proliferation, tissue remodeling, development, differentiation, inflammation, tumor progression, and invasion and controls vessel thickening in cardiovascular diseases. Therefore, the control of HA synthesis could permit the fine-tuning of cell behavior, but the mechanisms that regulate HA synthesis are largely unknown. Recent studies suggest that the availability of the nucleotide-sugar precursors has a critical role. Because the formation of UDP-sugars is a highly energetically demanding process, we have analyzed whether the energy status of the cell could control GAG production. AMP-activated protein kinase (AMPK) is the main ATP/AMP sensor of mammalian cells, and we mimicked an energy stress by treating human aortic smooth muscle cells (AoSMCs) with the AMPK activators 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside and metformin. Under these conditions, HA synthesis, but not that of the other GAGs, was greatly reduced. We confirmed the inhibitory effect of AMPK using a specific inhibitor and knock-out cell lines. We found that AMPK phosphorylated Thr-110 of human HAS2, which inhibits its enzymatic activity. In contrast, the other two HAS isoenzymes (HAS1 and HAS3) were not modified by the kinase. The reduction of HA decreased the ability of AoSMCs to proliferate, migrate, and recruit immune cells, thereby reducing the pro-atherosclerotic AoSMC phenotype. Interestingly, such effects were not recovered by treatment with exogenous HA, suggesting that AMPK can block the pro-atherosclerotic signals driven by HA by interaction with its receptors.
authors.affiliation: From the Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi dell'Insubria, Via J. H. Dunant 5, 21100 Varese, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Vigetti
authors.affiliation: From the Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi dell'Insubria, Via J. H. Dunant 5, 21100 Varese, Italy.
authors.forename: Moira
authors.initials: M
authors.lastname: Clerici
authors.affiliation: From the Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi dell'Insubria, Via J. H. Dunant 5, 21100 Varese, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Deleonibus
authors.affiliation: From the Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi dell'Insubria, Via J. H. Dunant 5, 21100 Varese, Italy.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Karousou
authors.affiliation: From the Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi dell'Insubria, Via J. H. Dunant 5, 21100 Varese, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Viola
authors.affiliation: From the Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi dell'Insubria, Via J. H. Dunant 5, 21100 Varese, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Moretto
authors.affiliation: the Ludwig Institute for Cancer Research, Uppsala University Biomedical Center, SE-75124 Uppsala, Sweden, and.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Heldin
authors.affiliation: the Department of Biomedical Engineering, The Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Hascall
authors.affiliation: From the Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi dell'Insubria, Via J. H. Dunant 5, 21100 Varese, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: De Luca
authors.affiliation: From the Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi dell'Insubria, Via J. H. Dunant 5, 21100 Varese, Italy,. Electronic address: alberto.passi@uninsubria.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Passi
mesh_terms: D055372:AMP-Activated Protein Kinases; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis* / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology
chemical_list: D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases; D055372:AMP-Activated Protein Kinases