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Maria Gomez

Maria Gomez

Professor

Maria Gomez

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

Author

  • Fabiana Blanco
  • Suvi E Heinonen
  • Erika Gurzeler
  • Lisa M Berglund
  • Anna-Maria Dutius Andersson
  • Olga Kotova
  • Ann-Cathrine Jönsson-Rylander
  • Seppo Ylä-Herttuala
  • Maria F Gomez

Summary, in English

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.

Department/s

  • EXODIAB: Excellence in Diabetes Research in Sweden
  • Diabetic Complications
  • StemTherapy: National Initiative on Stem Cells for Regenerative Therapy

Publishing year

2018-03-02

Language

English

Pages

302-313

Publication/Series

Diabetes and Vascular Disease Research

Volume

15

Issue

4

Document type

Journal article

Publisher

SAGE Publications

Topic

  • Cell and Molecular Biology

Keywords

  • Atherosclerosis
  • oxidative stress
  • type 2 diabetes
  • nuclear factor of activated T-cells
  • hyperglycaemia
  • ApoB100

Status

Published

Research group

  • Diabetic Complications

ISBN/ISSN/Other

  • ISSN: 1752-8984