In vivo inhibition of nuclear factor of activated t cells (NFAT) restores microvascular endothelial function in diabetic mice

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    Objectives: Central to the development of diabetic vascular disease is endothelial dysfunction, which appears well before any clinical sign, but importantly, is potentially reversible. Impaired endothelial function leads to increased vasoconstriction, inflammation and thrombosis, all of which predispose the vessels to atherosclerosis. We previously demonstrated that hyperglycemia activates NFAT in large and small arteries in vivo and that this promotes the expression of endothelial activation and inflammatory markers. Also, that blockade of NFAT signaling abolishes diabetes-driven aggravation of atherosclerosis in mice. Here we explored whether NFAT is involved in the development of diabetic microvascular dysfunction.

    Methods: NFAT-luciferase reporter male Akita (Ins2+/-) and non-diabetic littermate control mice were treated with the NFAT blocker A-285222 for 4 weeks (daily i.p. injections; 0.29mg/kg). Luciferase activity, microvascular function as assessed by Laser Doppler Imaging and iontophoresis responses to acetylcholine (Ach) and localized heating, and plasma cytokines were measured.

    Results: NFAT-transcriptional activity was elevated in aorta, cerebral, retinal and skin microvessels, as well as in the heart of diabetic (blood glucose >20 mmol/l) mice when compared to controls. Treatment with A-285222 inhibited NFAT-transcriptional activity in the vessels and heart and resulted in improved microvascular function, (Ach: p<0.05; Heat: p<0.01; vs. saline treated mice; n=15-20/group) which was abolished by pre-treatment with the nitric oxide synthase inhibitor L-NAME (20mg/kg i.p.). NFAT inhibition prevented a diabetes-driven increase in IL-6, sICAM and osteopontin, improved blood pressure and survival rate without affecting blood glucose or body weight.

    Conclusions: Inhibition of NFAT may represent a novel therapeutic approach for the treatment of diabetic microangiopathy.
    Original languageEnglish
    Article numberEAS16-0988
    Pages (from-to)e244-e245
    Number of pages2
    Early online date22 Sept 2016
    Publication statusPublished - Sept 2016


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