Limits...
Regulated Hyaluronan Synthesis by Vascular Cells.

Viola M, Karousou E, D'Angelo ML, Caon I, De Luca G, Passi A, Vigetti D - Int J Cell Biol (2015)

Bottom Line: Specific drugs reducing the UDP precursors are able to reduce HA synthesis whereas the hexosamine biosynthetic pathway (HBP) increases the concentration of HA precursor UDP-N-acetylglucosamine (UDP-GlcNAc) leading to an increase of HA synthesis.In fact, inhibiting O-GlcNAcylation reduced HA production whereas increased O-GlcNAcylation augmented HA secretion.Additionally, O-GlcNAcylation regulates HAS2 gene expression resulting in accumulation of its mRNA after induction of O-GlcNAcylation with glucosamine treatments.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgical and Morphological Sciences, University of Insubria, 21100 Varese, Italy.

ABSTRACT
Cellular microenvironment plays a critical role in several pathologies including atherosclerosis. Hyaluronan (HA) content often reflects the progression of this disease in promoting vessel thickening and cell migration. HA synthesis is regulated by several factors, including the phosphorylation of HA synthase 2 (HAS2) and other covalent modifications including ubiquitination and O-GlcNAcylation. Substrate availability is important in HA synthesis control. Specific drugs reducing the UDP precursors are able to reduce HA synthesis whereas the hexosamine biosynthetic pathway (HBP) increases the concentration of HA precursor UDP-N-acetylglucosamine (UDP-GlcNAc) leading to an increase of HA synthesis. The flux through the HBP in the regulation of HA biosynthesis in human aortic vascular smooth muscle cells (VSMCs) was reported as a critical aspect. In fact, inhibiting O-GlcNAcylation reduced HA production whereas increased O-GlcNAcylation augmented HA secretion. Additionally, O-GlcNAcylation regulates HAS2 gene expression resulting in accumulation of its mRNA after induction of O-GlcNAcylation with glucosamine treatments. The oxidized LDLs, the most common molecules related to atherosclerosis outcome and progression, are also able to induce a strong HA synthesis when they are in contact with vascular cells. In this review, we present recent described mechanisms involved in HA synthesis regulation and their role in atherosclerosis outcome and development.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the regulation of HA synthesis by OGT in SMCs. In normal conditions HAS2 in plasma membrane is active but can be rapidly degraded in a 26 S proteasome dependent manner. In hyperglycemic condition or after glucosamine treatments, OGT catalyzes the O-GlcNAcylation of HAS2 serine 221 residue, which greatly stabilizes HAS2 favoring HA production.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4581571&req=5

fig3: Schematic representation of the regulation of HA synthesis by OGT in SMCs. In normal conditions HAS2 in plasma membrane is active but can be rapidly degraded in a 26 S proteasome dependent manner. In hyperglycemic condition or after glucosamine treatments, OGT catalyzes the O-GlcNAcylation of HAS2 serine 221 residue, which greatly stabilizes HAS2 favoring HA production.

Mentions: Glucose is a major cell substrate, and its utilization is finely regulated allosterically as well as hormonally. HBP represents an alternative glucose pathway in the cells which leads to the formation of the crucial sugar nucleotide UDP-GlcNAc [44]. Besides being a substrate for HA and other glycoconjugate biosyntheses, UDP-GlcNAc is the substrate of O-GlcNAc transferase (OGT), the critical enzyme for protein O-GlcNAcylation [45], which is the reversible modification of nuclear or cytosolic proteins by attachment of a single β-GlcNAc moiety by O-linkage to specific serine/threonine residues. O-GlcNAcylation increased typically in hyperglycemic conditions, due to the entering of the excess of glucose in the HBP, and is involved in several diabetic complications [46–48]. As angiopathies are one of the main complications of diabetes and HA is altered in human diabetic patients [49] as well as in animal models of this pathology [50], it is not surprising that HA synthesis is induced by HAS2 O-GlcNAcylation (Figure 3) [39].


Regulated Hyaluronan Synthesis by Vascular Cells.

Viola M, Karousou E, D'Angelo ML, Caon I, De Luca G, Passi A, Vigetti D - Int J Cell Biol (2015)

Schematic representation of the regulation of HA synthesis by OGT in SMCs. In normal conditions HAS2 in plasma membrane is active but can be rapidly degraded in a 26 S proteasome dependent manner. In hyperglycemic condition or after glucosamine treatments, OGT catalyzes the O-GlcNAcylation of HAS2 serine 221 residue, which greatly stabilizes HAS2 favoring HA production.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4581571&req=5

fig3: Schematic representation of the regulation of HA synthesis by OGT in SMCs. In normal conditions HAS2 in plasma membrane is active but can be rapidly degraded in a 26 S proteasome dependent manner. In hyperglycemic condition or after glucosamine treatments, OGT catalyzes the O-GlcNAcylation of HAS2 serine 221 residue, which greatly stabilizes HAS2 favoring HA production.
Mentions: Glucose is a major cell substrate, and its utilization is finely regulated allosterically as well as hormonally. HBP represents an alternative glucose pathway in the cells which leads to the formation of the crucial sugar nucleotide UDP-GlcNAc [44]. Besides being a substrate for HA and other glycoconjugate biosyntheses, UDP-GlcNAc is the substrate of O-GlcNAc transferase (OGT), the critical enzyme for protein O-GlcNAcylation [45], which is the reversible modification of nuclear or cytosolic proteins by attachment of a single β-GlcNAc moiety by O-linkage to specific serine/threonine residues. O-GlcNAcylation increased typically in hyperglycemic conditions, due to the entering of the excess of glucose in the HBP, and is involved in several diabetic complications [46–48]. As angiopathies are one of the main complications of diabetes and HA is altered in human diabetic patients [49] as well as in animal models of this pathology [50], it is not surprising that HA synthesis is induced by HAS2 O-GlcNAcylation (Figure 3) [39].

Bottom Line: Specific drugs reducing the UDP precursors are able to reduce HA synthesis whereas the hexosamine biosynthetic pathway (HBP) increases the concentration of HA precursor UDP-N-acetylglucosamine (UDP-GlcNAc) leading to an increase of HA synthesis.In fact, inhibiting O-GlcNAcylation reduced HA production whereas increased O-GlcNAcylation augmented HA secretion.Additionally, O-GlcNAcylation regulates HAS2 gene expression resulting in accumulation of its mRNA after induction of O-GlcNAcylation with glucosamine treatments.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgical and Morphological Sciences, University of Insubria, 21100 Varese, Italy.

ABSTRACT
Cellular microenvironment plays a critical role in several pathologies including atherosclerosis. Hyaluronan (HA) content often reflects the progression of this disease in promoting vessel thickening and cell migration. HA synthesis is regulated by several factors, including the phosphorylation of HA synthase 2 (HAS2) and other covalent modifications including ubiquitination and O-GlcNAcylation. Substrate availability is important in HA synthesis control. Specific drugs reducing the UDP precursors are able to reduce HA synthesis whereas the hexosamine biosynthetic pathway (HBP) increases the concentration of HA precursor UDP-N-acetylglucosamine (UDP-GlcNAc) leading to an increase of HA synthesis. The flux through the HBP in the regulation of HA biosynthesis in human aortic vascular smooth muscle cells (VSMCs) was reported as a critical aspect. In fact, inhibiting O-GlcNAcylation reduced HA production whereas increased O-GlcNAcylation augmented HA secretion. Additionally, O-GlcNAcylation regulates HAS2 gene expression resulting in accumulation of its mRNA after induction of O-GlcNAcylation with glucosamine treatments. The oxidized LDLs, the most common molecules related to atherosclerosis outcome and progression, are also able to induce a strong HA synthesis when they are in contact with vascular cells. In this review, we present recent described mechanisms involved in HA synthesis regulation and their role in atherosclerosis outcome and development.

No MeSH data available.


Related in: MedlinePlus