IN VIVO INHIBITION OF NFAT SIGNALING RESTORES MICROVASCULAR ENDOTHELIAL FUNCTION IN DIABETIC MICE

Abstract

Vascular disease is the major cause of morbidity and mortality in diabetes. We previously demonstrated that hyperglycemia activates the transcription factor nuclear factor of activated T cells (NFAT) in large and small arteries in vivo and that this leads to enhanced expression of endothelial activation and inflammatory markers. Also, that in vivo blockade of NFAT signaling abolishes the diabetes-driven aggravation of atherosclerosis in mice. Here we explored whether NFAT is involved in the development of diabetic microvascular dysfunction. We found that NFAT-dependent transcriptional activity was elevated in aorta, cerebral, retinal and skin vessels, as well as in the heart of NFAT-luciferase reporter diabetic (blood glucose >20 mmol/l) male Akita (Ins2+/-) mice when compared to littermate non-diabetic mice. Treatment of diabetic mice with the NFAT blocker A-285222 for 4 weeks (daily i.p. injections; 0.29mg/kg) resulted in improved microvascular function, as assessed by Laser Doppler Imaging and iontophoresis responses to acetylcholine (Ach) and localized heating (Ach: p<0.05; Heat: p<0.01; vs. saline treated mice; n=15-20/group). This improvement was abolished by pre-treatment with the nitric oxide synthase inhibitor L-NAME (20mg/kg i.p.). Treatment with A-285222 inhibited NFAT-transcriptional activity in the vessels but had no effect on blood glucose. We propose inhibition of NFAT activity may therefore provide a novel therapeutic modality for the treatment of diabetic microangiopathy.