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Role of NFAT (nuclear factor of activated T cells) in vascular smooth muscle

Berglund, Lisa LU (2009) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2009:16.
Abstract
The calcium-dependent transcription factor NFAT was first described as a key player in immune cell regulation. Since then, NFAT signaling has been shown to be crucial for normal vascular development during embryogenesis. This pathway is also an important regulator of cell growth and differentiation in various cell types, however, the functional significance of NFAT in the vasculature is largely unclear.

Here, we show for the first time that NFAT is expressed in human arteries and that the novel NFAT blocker A-285222 prevents NFAT activation in this tissue. While NFAT inhibition had only minor effects on vascular contractility and expression of proteins associated with the contractile/cytoskeletal system, it resulted in decreased... (More)
The calcium-dependent transcription factor NFAT was first described as a key player in immune cell regulation. Since then, NFAT signaling has been shown to be crucial for normal vascular development during embryogenesis. This pathway is also an important regulator of cell growth and differentiation in various cell types, however, the functional significance of NFAT in the vasculature is largely unclear.

Here, we show for the first time that NFAT is expressed in human arteries and that the novel NFAT blocker A-285222 prevents NFAT activation in this tissue. While NFAT inhibition had only minor effects on vascular contractility and expression of proteins associated with the contractile/cytoskeletal system, it resulted in decreased interleukin-6 production in intact arteries. We provide evidence demonstrating that the NFATc3 isoform has an essential role in the regulation of vascular smooth muscle cell (VSMC) proliferation. NFAT affects VSMC proliferation via splicing of the allograft inflammatory factor-1 (AIF-1) gene. AIF-1 and interferon response transcript-1 (IRT-1) are alternative transcripts encoded from the AIF-1 gene and over expression of AIF-1 led to increased migration and proliferation of VSMCs, whereas IRT-1 over expression had the opposite effect. Moreover, AIF-1 over expression resulted in increased balloon injury-induced neointima formation in rat carotid arteries, whereas over expression of the anti-proliferative IRT-1 yielded less neointima. This suggests that the NFAT signaling pathway may be important for the VSMC response to injury.

We further show that a modest elevation in extracellular glucose concentrations led to increased NFAT activity. The mechanism by which glucose acts is via local release of extracellular nucleotides that activate P2Y receptors and increase calcium influx, and via inhibition of GSK-3b and JNK, which oppose NFAT activation. Incubation of arteries in high glucose led to increased expression of the pro-inflammatory cytokine osteopontin (OPN) in an NFAT-dependent manner. Furthermore, streptozotocin-induced diabetes was associated with increased NFAT activation and OPN expression in vivo. Diabetes-induced upregulation of OPN was effectively prevented by pharmacological inhibition of NFAT with A-285222, or in mice lacking NFATc3.

In summary, by responding to discrete elevations in blood glucose, NFAT may be of importance for the vascular response to hyperglycemia in diabetes. Combined with the described role for NFAT in the regulation of VSMC proliferation and cytokine expression, inhibition of NFAT signaling with A-285222 is a potential therapeutic target for preventing diabetic vascular complications. (Less)
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author
supervisor
opponent
  • PhD Bowles, Douglas K, Biomedical Sciences, Investigator, Dalton Cardiovascular Research Center, University of Missouri, Columbia
organization
publishing date
type
Thesis
publication status
published
subject
keywords
vascular smooth muscle, proliferation, A-285222, osteopontin, AIF-1, diabetes, vascular disease, calcium, glucose, NFAT
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2009:16
pages
126 pages
publisher
Department of Clinical Sciences, Lund University
defense location
Lilla aulan, Medical Research Center (MFC), Entrance 59, University Hospital UMAS
defense date
2009-02-27 09:15
ISSN
1652-8220
ISBN
978-91-86253-03-5
language
English
LU publication?
yes
id
f8ea220c-8461-44d3-9666-dd069454f40a (old id 1289049)
date added to LUP
2009-02-06 13:14:35
date last changed
2016-09-19 08:44:51
@phdthesis{f8ea220c-8461-44d3-9666-dd069454f40a,
  abstract     = {The calcium-dependent transcription factor NFAT was first described as a key player in immune cell regulation. Since then, NFAT signaling has been shown to be crucial for normal vascular development during embryogenesis. This pathway is also an important regulator of cell growth and differentiation in various cell types, however, the functional significance of NFAT in the vasculature is largely unclear. <br/><br>
Here, we show for the first time that NFAT is expressed in human arteries and that the novel NFAT blocker A-285222 prevents NFAT activation in this tissue. While NFAT inhibition had only minor effects on vascular contractility and expression of proteins associated with the contractile/cytoskeletal system, it resulted in decreased interleukin-6 production in intact arteries. We provide evidence demonstrating that the NFATc3 isoform has an essential role in the regulation of vascular smooth muscle cell (VSMC) proliferation. NFAT affects VSMC proliferation via splicing of the allograft inflammatory factor-1 (AIF-1) gene. AIF-1 and interferon response transcript-1 (IRT-1) are alternative transcripts encoded from the AIF-1 gene and over expression of AIF-1 led to increased migration and proliferation of VSMCs, whereas IRT-1 over expression had the opposite effect. Moreover, AIF-1 over expression resulted in increased balloon injury-induced neointima formation in rat carotid arteries, whereas over expression of the anti-proliferative IRT-1 yielded less neointima. This suggests that the NFAT signaling pathway may be important for the VSMC response to injury. <br/><br>
We further show that a modest elevation in extracellular glucose concentrations led to increased NFAT activity. The mechanism by which glucose acts is via local release of extracellular nucleotides that activate P2Y receptors and increase calcium influx, and via inhibition of GSK-3b and JNK, which oppose NFAT activation. Incubation of arteries in high glucose led to increased expression of the pro-inflammatory cytokine osteopontin (OPN) in an NFAT-dependent manner. Furthermore, streptozotocin-induced diabetes was associated with increased NFAT activation and OPN expression in vivo. Diabetes-induced upregulation of OPN was effectively prevented by pharmacological inhibition of NFAT with A-285222, or in mice lacking NFATc3. <br/><br>
In summary, by responding to discrete elevations in blood glucose, NFAT may be of importance for the vascular response to hyperglycemia in diabetes. Combined with the described role for NFAT in the regulation of VSMC proliferation and cytokine expression, inhibition of NFAT signaling with A-285222 is a potential therapeutic target for preventing diabetic vascular complications.},
  author       = {Berglund, Lisa},
  isbn         = {978-91-86253-03-5},
  issn         = {1652-8220},
  keyword      = {vascular smooth muscle,proliferation,A-285222,osteopontin,AIF-1,diabetes,vascular disease,calcium,glucose,NFAT},
  language     = {eng},
  pages        = {126},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Role of NFAT (nuclear factor of activated T cells) in vascular smooth muscle},
  volume       = {2009:16},
  year         = {2009},
}