on February 9, 2006
Published online before print February 9, 2006, doi: 10.1161/01.ATV.0000209513.00765.13
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Submitted on October 22, 2005
Accepted on January 18, 2006
High Glucose Activates Nuclear Factor of Activated T Cells in Native Vascular Smooth Muscle
Jenny Nilsson ;
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.
* To whom correspondence should be addressed. 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 3
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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