Endocrine Abstracts

Vascular disease is a major cause of morbidity and mortality in people who have diabetes. Hyperglycaemia is associated with increased transcriptional activity of nuclear factor of activated T cells (NFAT) in the vasculature. NFAT activation enhances expression of pro-inflammatory mediators including osteopontin, COX2 and IL6, implicated in the development of vascular disease. This study investigated the therapeutic potential of NFAT inhibition on the progression of microvascular dysfunction in Akita diabetic mice.

Male Akita diabetic mice (C57BL6-Ins 2; 8–10 weeks old) were randomly assigned to receive NFAT blocker (A-285222) or saline control (0.29 mg/kg i.p., n=15–20/group) for 4 weeks. Laser Doppler imaging and iontophoresis of acetylcholine (ACh) and response to localised heating was used to assess microvascular function in vivo. The nitric oxide (NO) synthase inhibitor L-NAME (20 mg/kg i.p.) was used to assess the role of endothelium-derived NO. Blood pressure was assessed non-invasively. Plasma cytokines levels were measured by ELISA.

All animals were chronically hyperglycaemic at baseline (blood glucose >20 mmol/l). Following 4 weeks’ intervention, inhibitor treated animals showed significantly greater vasodilator responses to ACh and heat (ACh: P<0.05 vs Control; Heat P<0.01 vs Control). This improvement was abolished by pre-treatment with L-NAME. Treatment with A-285222 significantly reduced plasma levels of IL6, and osteopontin when compared with vehicle treated animals. Blood pressure was significantly lower in inhibitor treated animals (Control: 125±4.7 vs Inhibitor: 83.9±7.9 mm/Hg P<0.05) and was negatively correlated with ACh response (r=−0.629; P<0.05).

Inhibition of NFAT attenuated the deterioration of endothelial function and blood pressure associated with diabetes. These effects were abolished by L-NAME suggesting a role for NO. Furthermore, improvements in endothelial function and blood pressure were accompanied by a marked reduction in circulating cytokine levels suggesting a role of inflammation-induced endothelial dysfunction. Inhibition of NFAT activity may therefore provide a novel therapeutic modality for the treatment of microangiopathy associated with chronic diabetes.