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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 HAS2 expression by OGT in SMCs. In normal conditions, basal HAS2 and HAS2-AS1 expression are allowed. After the induction of O-GlcNAcylation (due to hyperglycemia or after glucosamine treatments), the NF-κB subunit RelA can be modified with O-GlcNAc by OGT. In the cell nucleus, glycosylated RelA can activate HAS2-AS1 transcription, which, in turn, changes chromatin structure around the HAS2 promoter (probably altering chromatin signature) favoring HAS2 expression leading to HA accumulation.
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fig4: Schematic representation of the regulation of HAS2 expression by OGT in SMCs. In normal conditions, basal HAS2 and HAS2-AS1 expression are allowed. After the induction of O-GlcNAcylation (due to hyperglycemia or after glucosamine treatments), the NF-κB subunit RelA can be modified with O-GlcNAc by OGT. In the cell nucleus, glycosylated RelA can activate HAS2-AS1 transcription, which, in turn, changes chromatin structure around the HAS2 promoter (probably altering chromatin signature) favoring HAS2 expression leading to HA accumulation.

Mentions: O-GlcNAcylation is also able to modulate gene expression, and in VSMCs this glycosylation leads to an increment of HAS2 mRNA [52]. The molecular mechanism of such regulation is complex and does not involve the typical O-GlcNAcylated transcription factors that are known to regulate HA synthesis like YY1 and SP1, which are able to interact with the HAS2 promoter [13]. By using ChIP analyses from mice with high O-GlcNAcylation levels, we found a significant signal in correspondence with the natural antisense transcript for HAS2 (HAS2-AS1), which is a particular long noncoding RNA transcribed using the opposite strand of HAS2 locus on chromosome 8 [53]. HAS2 and HAS2-AS1 RNA molecules share about 200 base pairs and can form a RNA:RNA duplex. In previous papers antisense transcripts have been described to stabilize their sense mRNA [54, 55], but this mechanism did not work with VSMCs. In contrast, we found that HAS2-AS1 transcription is initiated by O-GlcNAcylation of RelA (a component of NF-κB complex) [56], and HAS2-AS1 was necessary to change chromatin structure around the HAS2 promoter to allow more efficient binding of RNA polymerase 2, thereby enhancing HAS2 gene expression (Figure 4) [52]. In vivo analyses confirmed the crucial role of HAS2-AS1 in the regulation of HAS2 in humans and in animal models for vascular pathologies [52]. Although investigations are still in progress, our hypothesis is that HAS2-AS1 could alter the epigenetic signature of the HAS2 promoter by switching it into a more active chromatin. The more recent theories about the long noncoding RNA functions highlight their role in recruiting enzymes able to modify histones and DNA in particular loci of the genome [57–60].


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 HAS2 expression by OGT in SMCs. In normal conditions, basal HAS2 and HAS2-AS1 expression are allowed. After the induction of O-GlcNAcylation (due to hyperglycemia or after glucosamine treatments), the NF-κB subunit RelA can be modified with O-GlcNAc by OGT. In the cell nucleus, glycosylated RelA can activate HAS2-AS1 transcription, which, in turn, changes chromatin structure around the HAS2 promoter (probably altering chromatin signature) favoring HAS2 expression leading to HA accumulation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Schematic representation of the regulation of HAS2 expression by OGT in SMCs. In normal conditions, basal HAS2 and HAS2-AS1 expression are allowed. After the induction of O-GlcNAcylation (due to hyperglycemia or after glucosamine treatments), the NF-κB subunit RelA can be modified with O-GlcNAc by OGT. In the cell nucleus, glycosylated RelA can activate HAS2-AS1 transcription, which, in turn, changes chromatin structure around the HAS2 promoter (probably altering chromatin signature) favoring HAS2 expression leading to HA accumulation.
Mentions: O-GlcNAcylation is also able to modulate gene expression, and in VSMCs this glycosylation leads to an increment of HAS2 mRNA [52]. The molecular mechanism of such regulation is complex and does not involve the typical O-GlcNAcylated transcription factors that are known to regulate HA synthesis like YY1 and SP1, which are able to interact with the HAS2 promoter [13]. By using ChIP analyses from mice with high O-GlcNAcylation levels, we found a significant signal in correspondence with the natural antisense transcript for HAS2 (HAS2-AS1), which is a particular long noncoding RNA transcribed using the opposite strand of HAS2 locus on chromosome 8 [53]. HAS2 and HAS2-AS1 RNA molecules share about 200 base pairs and can form a RNA:RNA duplex. In previous papers antisense transcripts have been described to stabilize their sense mRNA [54, 55], but this mechanism did not work with VSMCs. In contrast, we found that HAS2-AS1 transcription is initiated by O-GlcNAcylation of RelA (a component of NF-κB complex) [56], and HAS2-AS1 was necessary to change chromatin structure around the HAS2 promoter to allow more efficient binding of RNA polymerase 2, thereby enhancing HAS2 gene expression (Figure 4) [52]. In vivo analyses confirmed the crucial role of HAS2-AS1 in the regulation of HAS2 in humans and in animal models for vascular pathologies [52]. Although investigations are still in progress, our hypothesis is that HAS2-AS1 could alter the epigenetic signature of the HAS2 promoter by switching it into a more active chromatin. The more recent theories about the long noncoding RNA functions highlight their role in recruiting enzymes able to modify histones and DNA in particular loci of the genome [57–60].

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