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

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

In: Diabetes and Vascular Disease Research, Vol. 15, No. 4, 2018, p. 302-313.

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Blanco, Fabiana ; Heinonen, Suvi E ; Gurzeler, Erika ; Berglund, Lisa M ; Dutius Andersson, Anna-Maria ; Kotova, Olga ; Jönsson-Rylander, Ann-Cathrine ; Ylä-Herttuala, Seppo ; Gomez, Maria F. / In vivo inhibition of nuclear factor of activated T-cells leads to atherosclerotic plaque regression in IGF-II/LDLR -/-ApoB100/100 mice. In: Diabetes and Vascular Disease Research. 2018 ; Vol. 15, No. 4. pp. 302-313.

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TY - JOUR

T1 - In vivo inhibition of nuclear factor of activated T-cells leads to atherosclerotic plaque regression in IGF-II/LDLR -/-ApoB100/100 mice

AU - Blanco, Fabiana

AU - Heinonen, Suvi E

AU - Gurzeler, Erika

AU - Berglund, Lisa M

AU - Dutius Andersson, Anna-Maria

AU - Kotova, Olga

AU - Jönsson-Rylander, Ann-Cathrine

AU - Ylä-Herttuala, Seppo

AU - Gomez, Maria F

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - oxidative stress

KW - type 2 diabetes

KW - nuclear factor of activated T-cells

KW - hyperglycaemia

KW - ApoB100

U2 - 10.1177/1479164118759220

DO - 10.1177/1479164118759220

M3 - Article

C2 - 29499628

VL - 15

SP - 302

EP - 313

JO - Diabetes and Vascular Disease Research

JF - Diabetes and Vascular Disease Research

SN - 1752-8984

IS - 4

ER -