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

Research output: Contribution to journalArticle

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 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.

Details

Authors
Organisations
External organisations
  • University of the Republic
  • AstraZeneca, Sweden
  • University of Eastern Finland
  • Kuopio University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • Atherosclerosis, oxidative stress, type 2 diabetes, nuclear factor of activated T-cells, hyperglycaemia, ApoB100
Original languageEnglish
Pages (from-to)302-313
JournalDiabetes and Vascular Disease Research
Volume15
Issue number4
Early online date2018 Mar 2
Publication statusPublished - 2018
Publication categoryResearch
Peer-reviewedYes

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