Objective: Diabetes is associated with devastating macrovascular complications including coronary heart disease and stroke. The molecular mechanisms leading to vascular disease are still poorly understood. We have previously shown that hyperglycemia activates the transcription factor NFAT in native arteries. Once activated, NFAT promotes cell proliferation, enhances SMC excitability and the expression of inflammatory markers (i.e. IL-6, tissue factor, COX-2). Here we tested whether NFAT is involved in the development of macrovascular disease. Results and methods: Treatment of ApoE KO mice with streptozotocin (STZ) led to hyperglycemia, elevated plasma cholesterol and triglycerides. STZ-treatment resulted in 119% increased aortic atherosclerosis, enhanced expression of the pro- atherosclerotic protein osteopontin (OPN) in subvalvular aortic lesions and increased plasma OPN. Four weeks treatment of diabetic mice with the NFAT blocker A-285222 completely inhibited the hyperglycemia induced aggravation of atherosclerosis, but had no effect on atherosclerosis in non-diabetic mice. Body weight and levels of inflammatory cytokines were not affected by A-285222 treatment, suggesting that the reduced atherosclerosis is less likely due to systemic immunosuppression. Conclusion: Our results provide evidence for the involvement of NFAT in the development of macrovascular complications in diabetes. Sources of funding: Swedish Heart & Lung Foundations & Research Medical Council