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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 the regulation of HA synthesis in ECs and the effects on immune cell-EC adhesion. Through their receptors, proinflammatory signals (i.e., cytokines) trigger NF-κB pathway that regulates both HAS2 and CD44 (and other adhesive molecules such as ICAM-1, E-selectin, VCAM-1, and MHC class I genes) [38]. HAS2 synthesizes high molecular weight HA that interacts with CD44 present on both ECs and immune cells (i.e., leukocytes) in the “sandwich model,” which drives immune cells to adhere to ECs contributing to inflammation. Gray circle represents the nucleus.
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fig1: Schematic representation of the regulation of HA synthesis in ECs and the effects on immune cell-EC adhesion. Through their receptors, proinflammatory signals (i.e., cytokines) trigger NF-κB pathway that regulates both HAS2 and CD44 (and other adhesive molecules such as ICAM-1, E-selectin, VCAM-1, and MHC class I genes) [38]. HAS2 synthesizes high molecular weight HA that interacts with CD44 present on both ECs and immune cells (i.e., leukocytes) in the “sandwich model,” which drives immune cells to adhere to ECs contributing to inflammation. Gray circle represents the nucleus.

Mentions: HA synthesis has been found to be inducible in EC cultures, and its synthesis is triggered by proinflammatory mediators such as IL-1β, IL15, TNF-α, and lipopolysaccharide [35]. The increased secretion of HA during inflammation is due to the overexpression of the isoenzyme HAS2 [21, 36]. The cellular pathway that leads to HAS2 expression involves a NF-κB pathway. Increased HA, together with an augment of the typical adhesion molecules, is responsible for the increased binding of immune cells to ECs and is critical for regulating tissue inflammation. Interestingly, CD44 is also overexpressed in ECs treated with proinflammatory mediators, suggesting a particular model of EC/immune cell interaction. In this model, newly synthesized HA would be kept above the endothelium by CD44, and leukocytes would be bound to HA through their own CD44 [37]. Thus, this model highlights the importance of HA synthesis and confirms the critical role of HAS2 in triggering HA synthesis after proinflammatory signal treatments. Figure 1 summarizes the concepts expressed in this paragraph. Together with the alteration of the basal membrane, HA deposition seems therefore to be the earliest signal of the onset of a vascular disease.


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 in ECs and the effects on immune cell-EC adhesion. Through their receptors, proinflammatory signals (i.e., cytokines) trigger NF-κB pathway that regulates both HAS2 and CD44 (and other adhesive molecules such as ICAM-1, E-selectin, VCAM-1, and MHC class I genes) [38]. HAS2 synthesizes high molecular weight HA that interacts with CD44 present on both ECs and immune cells (i.e., leukocytes) in the “sandwich model,” which drives immune cells to adhere to ECs contributing to inflammation. Gray circle represents the nucleus.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Schematic representation of the regulation of HA synthesis in ECs and the effects on immune cell-EC adhesion. Through their receptors, proinflammatory signals (i.e., cytokines) trigger NF-κB pathway that regulates both HAS2 and CD44 (and other adhesive molecules such as ICAM-1, E-selectin, VCAM-1, and MHC class I genes) [38]. HAS2 synthesizes high molecular weight HA that interacts with CD44 present on both ECs and immune cells (i.e., leukocytes) in the “sandwich model,” which drives immune cells to adhere to ECs contributing to inflammation. Gray circle represents the nucleus.
Mentions: HA synthesis has been found to be inducible in EC cultures, and its synthesis is triggered by proinflammatory mediators such as IL-1β, IL15, TNF-α, and lipopolysaccharide [35]. The increased secretion of HA during inflammation is due to the overexpression of the isoenzyme HAS2 [21, 36]. The cellular pathway that leads to HAS2 expression involves a NF-κB pathway. Increased HA, together with an augment of the typical adhesion molecules, is responsible for the increased binding of immune cells to ECs and is critical for regulating tissue inflammation. Interestingly, CD44 is also overexpressed in ECs treated with proinflammatory mediators, suggesting a particular model of EC/immune cell interaction. In this model, newly synthesized HA would be kept above the endothelium by CD44, and leukocytes would be bound to HA through their own CD44 [37]. Thus, this model highlights the importance of HA synthesis and confirms the critical role of HAS2 in triggering HA synthesis after proinflammatory signal treatments. Figure 1 summarizes the concepts expressed in this paragraph. Together with the alteration of the basal membrane, HA deposition seems therefore to be the earliest signal of the onset of a vascular disease.

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