Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice

Abstract

Objective of the StudyDiabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis.Methodology and Principal FindingsStreptozotocin (STZ)-induced diabetes in apolipoprotein E−/− mice resulted in 2.2 fold increased aortic atherosclerosis and enhanced pro-inflammatory burden, as evidenced by elevated blood monocytes, endothelial activation- and inflammatory markers in aorta, and pro-inflammatory cytokines in plasma. In vivo treatment with the NFAT blocker A-285222 for 4 weeks completely inhibited the diabetes-induced aggravation of atherosclerosis, having no effect in non-diabetic mice. STZ-treated mice exhibited hyperglycemia and higher plasma cholesterol and triglycerides, but these were unaffected by A-285222. NFAT-dependent transcriptional activity was examined in aorta, spleen, thymus, brain, heart, liver and kidney, but only augmented in the aorta of diabetic mice. A-285222 completely blocked this diabetes-driven NFAT activation, but had no impact on the other organs or on splenocyte proliferation or cytokine secretion, ruling out systemic immunosuppression as the mechanism behind reduced atherosclerosis. Instead, NFAT inhibition effectively reduced IL-6, osteopontin, monocyte chemotactic protein 1, intercellular adhesion molecule 1, CD68 and tissue factor expression in the arterial wall and lowered plasma IL-6 in diabetic mice.ConclusionsTargeting NFAT signaling may be a novel and attractive approach for the treatment of diabetic macrovascular complications.

Nuclear Factor of Activated T Cells Regulates Neutrophil Recruitment, Systemic Inflammation, and T-Cell Dysfunction in Abdominal Sepsis

“…Considering that NFAT activity is regulated by calcineurin (45), our findings might help explain these inhibitory effects of calcineurin inhibitors on endotoxemia and pulmonary injury. Collectively, our data suggest a pathological role for the calcium/ calcineurin-NFAT signaling axis in the development of septic lung damage similar to that proposed for the development of cardiac hypertrophy (22), diabetes-induced vascular inflammation (46), atherosclerosis (39,47), and acute pancreatitis (24). HMGB1 and IL-6 are potent proinflammatory cytokines and markers of systemic inflammation in endotoxemia and sepsis (48,49).…”

“…NFAT activity is generally considered to control aspects of tissue development during embryogenesis, including vasculogenesis, axonal outgrowth, muscle and bone formation, as well as maturation of the immune system (34)(35)(36)(37)(38). However, a growing body of literature also implicates NFAT signaling in inflammatory processes, such as atherosclerosis (39), autoimmune diseases (40), and acute pancreatitis (24). Here, we show that in vivo administration of the NFAT inhibitor (A-285222) readily blocked sepsis-induced NFAT-dependent tran- scriptional activity not only in the lung but also in the spleen, liver, and aorta, suggesting not only that NFAT is activated in sepsis but also that A-285222 is an effective inhibitor of NFAT.…”

The role of DNA damage and repair in atherosclerosis: A review

“…This study succeeded earlier work which demonstrated that microRNA miR-204 down-regulation with subsequent up-regulation of anti-apoptotic and pro-proliferative transcription factors, nuclear factor of activated T Cells (NFAT) and hypoxia-inducible factor 1α (HIF-1α), correlated closely with PAH severity (122). Indeed, NFAT signaling has been implicated in adverse vascular remodeling post injury and atherosclerotic progression in diabetic mice (123,124). HIF-1α, on the other hand, is activated by a hypoxic ROS environment and has been shown to induce expression of vascular endothelial growth factor, thereby promoting VSMC proliferation (125) and subsequent atherosclerosis (126).…”

Elevated Glucose Levels Promote Contractile and Cytoskeletal Gene Expression in Vascular Smooth Muscle via Rho/Protein Kinase C and Actin Polymerization

“…In agreement with our results, previous reports have demonstrated that osteopontin is induced by hyperglycemia in smooth muscle cells. Several mechanisms have been proposed, including activation of the PKC/Rho-kinase pathway (62) and activation of the transcription factor NFATc3 (63,64). Thus, hyperglycemia in diabetic patients may result in simultaneous activation of the contractile and synthetic gene programs, leading to increased risk of neointimal hyperplasia as well as hypertension and vasospasm.…”