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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:794.)
© 2006 American Heart Association, Inc.

Vascular Biology

High Glucose Activates Nuclear Factor of Activated T Cells in Native Vascular Smooth Muscle

Jenny Nilsson; Lisa M. Nilsson; Yung-Wu Chen; Jeffery D. Molkentin; David Erlinge; Maria F. Gomez

From the Departments of Experimental Medical Science (J.N., L.M.N., M.F.G.) and Clinical Sciences (D.E.), Lund University, Sweden; Global Pharmaceutical Research and Development (Y.-W.C.), Abbott Laboratories, Abbott Park, Ill; and Department of Pediatrics (J.D.M.), Children’s Hospital Medical Center, Cincinnati, Ohio.

Correspondence to Maria F. Gomez, Department of Experimental Medical Science, BMC F12, SE-221 84 Lund, Sweden. E-mail maria.gomez{at}med.lu.se

Objective— Hyperglycemia has been suggested to play a role in the development of vascular disease associated with diabetes. Atypical Ca²⁺ signaling and gene expression are characteristic of vascular dysfunction; however, little is known regarding the effects of high glucose on Ca²⁺-dependent transcription in the vascular wall.

Methods and Results— Using confocal immunofluorescence, we show that modest elevation of extracellular glucose (ie, from 2 to 11.5 mmol/L) increased [Ca²⁺]_i, leading to nuclear accumulation of nuclear factor of activated T cells (NFAT) in intact cerebral arteries from mouse. This was accompanied by increased NFAT-dependent transcriptional activity. Both the increase in Ca²⁺ and NFAT activation were prevented by the ectonucleotidase apyrase, suggesting a mechanism involving the release of extracellular nucleotides. We provide evidence that the potent vasoconstrictors and growth stimulators UTP and UDP mediate glucose-induced NFAT activation via P2Y receptors. NFAT nuclear accumulation was inhibited by the voltage-dependent Ca²⁺ channel blockers verapamil and nifedipine, the calcineurin inhibitor cyclosporine A, and the novel NFAT blocker A-285222. High glucose also regulated glycogen synthase kinase 3ß and c-Jun N-terminal kinase activity, yielding decreased kinase activity and reduced export of NFAT from the nucleus, providing additional mechanisms underlying the glucose-induced NFAT activation.

Conclusions— Our results identify the calcineurin/NFAT signaling pathway as a potential metabolic sensor for the arterial smooth muscle response to high glucose.

Key Words: NFAT • high glucose • vascular smooth muscle • extracellular nucleotides • GSK-3

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