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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 HA metabolism in SMCs loaded with oxidized LDL (oxLDL). Nontoxic concentrations of oxLDL are driven inside the SMCs by the upregulation of the scavenger receptor LOX-1. Accumulation of oxLDL leads to ER stress with overexpression of the UPR factors CHOP and GRP78 as well as activation of the LXR sterol sensor system. One or both systems induce the overexpression in the nucleus of several genes: LOX-1, HAS2, and HAS3. The HASs are active on the plasma membrane where they synthesize HA that interacts with CD44 present on immune cells, driving their adhesion, which contributes to the inflammatory status of the atherosclerotic lesion.
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fig5: Schematic representation of HA metabolism in SMCs loaded with oxidized LDL (oxLDL). Nontoxic concentrations of oxLDL are driven inside the SMCs by the upregulation of the scavenger receptor LOX-1. Accumulation of oxLDL leads to ER stress with overexpression of the UPR factors CHOP and GRP78 as well as activation of the LXR sterol sensor system. One or both systems induce the overexpression in the nucleus of several genes: LOX-1, HAS2, and HAS3. The HASs are active on the plasma membrane where they synthesize HA that interacts with CD44 present on immune cells, driving their adhesion, which contributes to the inflammatory status of the atherosclerotic lesion.

Mentions: Several scavenger receptors have been reported to be able to internalize oxLDL (e.g., SR-PSOX, SR-AI, CD36, LOX-1, and LRP1). However, even though some of them are present on the SMC membrane, only LOX-1 was upregulated after oxLDL exposure [68, 69]. The oxLDL entrance via LOX-1 has various effects inside the cells: upregulation of LOX-1, increasing the load of lipids and ROS in ER leading to ER stress, and overexpression of HAS2 and HAS3 with concomitant deposition of HA in the ECM (Figure 5), all of which occur during atherosclerosis progression. The increase in HA in the SMC ECM promotes macrophage adhesion and activation as well as their higher migration ability.


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 HA metabolism in SMCs loaded with oxidized LDL (oxLDL). Nontoxic concentrations of oxLDL are driven inside the SMCs by the upregulation of the scavenger receptor LOX-1. Accumulation of oxLDL leads to ER stress with overexpression of the UPR factors CHOP and GRP78 as well as activation of the LXR sterol sensor system. One or both systems induce the overexpression in the nucleus of several genes: LOX-1, HAS2, and HAS3. The HASs are active on the plasma membrane where they synthesize HA that interacts with CD44 present on immune cells, driving their adhesion, which contributes to the inflammatory status of the atherosclerotic lesion.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: Schematic representation of HA metabolism in SMCs loaded with oxidized LDL (oxLDL). Nontoxic concentrations of oxLDL are driven inside the SMCs by the upregulation of the scavenger receptor LOX-1. Accumulation of oxLDL leads to ER stress with overexpression of the UPR factors CHOP and GRP78 as well as activation of the LXR sterol sensor system. One or both systems induce the overexpression in the nucleus of several genes: LOX-1, HAS2, and HAS3. The HASs are active on the plasma membrane where they synthesize HA that interacts with CD44 present on immune cells, driving their adhesion, which contributes to the inflammatory status of the atherosclerotic lesion.
Mentions: Several scavenger receptors have been reported to be able to internalize oxLDL (e.g., SR-PSOX, SR-AI, CD36, LOX-1, and LRP1). However, even though some of them are present on the SMC membrane, only LOX-1 was upregulated after oxLDL exposure [68, 69]. The oxLDL entrance via LOX-1 has various effects inside the cells: upregulation of LOX-1, increasing the load of lipids and ROS in ER leading to ER stress, and overexpression of HAS2 and HAS3 with concomitant deposition of HA in the ECM (Figure 5), all of which occur during atherosclerosis progression. The increase in HA in the SMC ECM promotes macrophage adhesion and activation as well as their higher migration ability.

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