Patients with diabetes have a much more widespread and aggressive form of atherosclerosis in the coronary arteries, lower extremities and extracranial carotid arteries, causing nearly 80% of all deaths and much of the disability in these patients (1). Diabetes type 1 and 2 are independent risk factors for myocardial infarction, peripheral vascular disease and stroke, also worsening their early and late outcomes, increasing the risk of recurrence and leading to poorer prognosis following surgical revascularization procedures. Despite the vast clinical experience linking diabetes and atherosclerosis, very little is understood about the molecular mechanisms connecting hyperglycemia to atherosclerosis. The nuclear factor of activated T-cells (NFATc1-c4) are a family of Ca2+/calcineurin-dependent transcription factors first characterized in T-lymphocytes as inducers of cytokine gene expression. Since then, NFAT proteins have been shown to play various roles outside immune cells, including in the cardiovascular system (2). We have previously shown that modest elevations of extracellular glucose effectively activate NFATc3 in vascular smooth muscle cells (VSMC) of large arteries (aorta and cerebral) and in small (retinal) microvessels in mice, both ex vivo and in vivo (3; 4). This effect involves the local release of extracellular nucleotides, such as UTP and UDP, acting on purinergic-2Y receptors, leading to increased [Ca2+]i and subsequent activation of calcineurin and NFATc3. In addition to promoting NFATc3 nuclear translocation, high glucose also reduces nuclear export of NFAT by inhibiting GSK-3β and JNK, providing additional mechanisms for glucose-induced NFAT activation. Once activated, NFAT promotes the expression of osteopontin (OPN). Diabetic mice showed increased expression of OPN in the ascending and thoracic aorta, vascular segments particularly prone to development of atherosclerosis and this was prevented by in vivo treatment with the NFAT inhibitor A-285222 or by lack of NFATc3 protein in arteries from NFATc3-/- mice. Additional experimental evidence supports a role for NFAT as a regulator of genes able to promote vascular dysfunction and potentially, a pro-atherogenic vascular phenotype. NFAT promotes VSMC proliferation and migration, and plays a role in neointima formation and in the regulation of cyclooxygenase 2 (Cox2) and RCAN1 expression after vascular injury (5). NFAT contributes to the development of angiotensin II-induced hypertension, via down-regulation of potassium channel expression (6). Moreover, NFAT controls the alternative splicing of allograft inflammatory factor-1 (AIF-1), resulting in products differentially associated to parameters defining human plaque phenotype and stability (7). Together, these observations led us to hypothesize that NFAT may act as a glucose-sensor in the vessel wall, translating changes in Ca2+ signals into changes in gene expression that lead to macrovascular disease in diabetes. To more directly test this hypothesis and in the context of an atherosclerosis-prone experimental model, we investigate the effects of NFAT-signaling inhibition on atherosclerotic plaque formation and inflammatory burden in diabetic and non-diabetic apolipoprotein (Apo)E deficient mice. We found that inhibition of NFAT-signaling completely suppresses the diabetes-induced aggravation of atherosclerosis, also effectively reducing the expression of OPN, MCP-1, IL-6, ICAM-1 and tissue factor in the arterial wall. This effect was independent of changes in plasma glucose or lipid levels, and not due to systemic immunosuppression. These findings suggest that NFAT may play a role in the development of atherosclerosis in diabetes and identifies this signaling pathway as a novel therapeutic target for the treatment of diabetic macrovascular complications.