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In vivo inhibition of nuclear factor of activated T-cells leads to atherosclerotic plaque regression in IGF-II/LDLR -/-ApoB100/100 mice

Blanco, Fabiana LU ; Heinonen, Suvi E ; Gurzeler, Erika ; Berglund, Lisa M LU ; Dutius Andersson, Anna-Maria LU ; Kotova, Olga LU ; Jönsson-Rylander, Ann-Cathrine ; Ylä-Herttuala, Seppo and Gomez, Maria F LU orcid (2018) In Diabetes and Vascular Disease Research 15(4). p.302-313
Abstract

AIMS: Despite vast clinical experience linking diabetes and atherosclerosis, the molecular mechanisms leading to accelerated vascular damage are still unclear. Here, we investigated the effects of nuclear factor of activated T-cells inhibition on plaque burden in a novel mouse model of type 2 diabetes that better replicates human disease.

METHODS & RESULTS: IGF-II/LDLR-/-ApoB100/100mice were generated by crossbreeding low-density lipoprotein receptor-deficient mice that synthesize only apolipoprotein B100 (LDLR-/-ApoB100/100) with transgenic mice overexpressing insulin-like growth factor-II in pancreatic β cells. Mice have mild hyperglycaemia and hyperinsulinaemia and develop complex atherosclerotic lesions. In vivo treatment... (More)

AIMS: Despite vast clinical experience linking diabetes and atherosclerosis, the molecular mechanisms leading to accelerated vascular damage are still unclear. Here, we investigated the effects of nuclear factor of activated T-cells inhibition on plaque burden in a novel mouse model of type 2 diabetes that better replicates human disease.

METHODS & RESULTS: IGF-II/LDLR-/-ApoB100/100mice were generated by crossbreeding low-density lipoprotein receptor-deficient mice that synthesize only apolipoprotein B100 (LDLR-/-ApoB100/100) with transgenic mice overexpressing insulin-like growth factor-II in pancreatic β cells. Mice have mild hyperglycaemia and hyperinsulinaemia and develop complex atherosclerotic lesions. In vivo treatment with the nuclear factor of activated T-cells blocker A-285222 for 4 weeks reduced atherosclerotic plaque area and degree of stenosis in the brachiocephalic artery of IGF-II/LDLR-/-ApoB100/100mice, as assessed non-invasively using ultrasound biomicroscopy prior and after treatment, and histologically after termination. Treatment had no impact on plaque composition (i.e. muscle, collagen, macrophages). The reduced plaque area could not be explained by effects of A-285222 on plasma glucose, insulin or lipids. Inhibition of nuclear factor of activated T-cells was associated with increased expression of atheroprotective NOX4 and of the anti-oxidant enzyme catalase in aortic vascular smooth muscle cells.

CONCLUSION: Targeting the nuclear factor of activated T-cells signalling pathway may be an attractive approach for the treatment of diabetic macrovascular complications.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Atherosclerosis, oxidative stress, type 2 diabetes, nuclear factor of activated T-cells, hyperglycaemia, ApoB100
in
Diabetes and Vascular Disease Research
volume
15
issue
4
pages
302 - 313
publisher
SAGE Publications
external identifiers
  • pmid:29499628
  • scopus:85049847334
ISSN
1752-8984
DOI
10.1177/1479164118759220
language
English
LU publication?
yes
id
48b1ec95-19ce-417e-a78b-20c8064de789
date added to LUP
2018-03-15 09:54:56
date last changed
2025-01-07 06:20:48
@article{48b1ec95-19ce-417e-a78b-20c8064de789,
  abstract     = {{<p>AIMS: Despite vast clinical experience linking diabetes and atherosclerosis, the molecular mechanisms leading to accelerated vascular damage are still unclear. Here, we investigated the effects of nuclear factor of activated T-cells inhibition on plaque burden in a novel mouse model of type 2 diabetes that better replicates human disease.</p><p>METHODS &amp; RESULTS: IGF-II/LDLR-/-ApoB100/100mice were generated by crossbreeding low-density lipoprotein receptor-deficient mice that synthesize only apolipoprotein B100 (LDLR-/-ApoB100/100) with transgenic mice overexpressing insulin-like growth factor-II in pancreatic β cells. Mice have mild hyperglycaemia and hyperinsulinaemia and develop complex atherosclerotic lesions. In vivo treatment with the nuclear factor of activated T-cells blocker A-285222 for 4 weeks reduced atherosclerotic plaque area and degree of stenosis in the brachiocephalic artery of IGF-II/LDLR-/-ApoB100/100mice, as assessed non-invasively using ultrasound biomicroscopy prior and after treatment, and histologically after termination. Treatment had no impact on plaque composition (i.e. muscle, collagen, macrophages). The reduced plaque area could not be explained by effects of A-285222 on plasma glucose, insulin or lipids. Inhibition of nuclear factor of activated T-cells was associated with increased expression of atheroprotective NOX4 and of the anti-oxidant enzyme catalase in aortic vascular smooth muscle cells.</p><p>CONCLUSION: Targeting the nuclear factor of activated T-cells signalling pathway may be an attractive approach for the treatment of diabetic macrovascular complications.</p>}},
  author       = {{Blanco, Fabiana and Heinonen, Suvi E and Gurzeler, Erika and Berglund, Lisa M and Dutius Andersson, Anna-Maria and Kotova, Olga and Jönsson-Rylander, Ann-Cathrine and Ylä-Herttuala, Seppo and Gomez, Maria F}},
  issn         = {{1752-8984}},
  keywords     = {{Atherosclerosis; oxidative stress; type 2 diabetes; nuclear factor of activated T-cells; hyperglycaemia; ApoB100}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{4}},
  pages        = {{302--313}},
  publisher    = {{SAGE Publications}},
  series       = {{Diabetes and Vascular Disease Research}},
  title        = {{<i>In vivo</i> inhibition of nuclear factor of activated T-cells leads to atherosclerotic plaque regression in IGF-II/LDLR <sup>-/-</sup>ApoB<sup>100/100</sup> mice}},
  url          = {{http://dx.doi.org/10.1177/1479164118759220}},
  doi          = {{10.1177/1479164118759220}},
  volume       = {{15}},
  year         = {{2018}},
}