High glucose activates nuclear factor of activated T cells in native vascular smooth muscle.
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.


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 3beta 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.
Nilsson
Jenny
J
Department of Experimental Medical Science, Lund University, Sweden.
Nilsson
Lisa M
LM
Chen
Yung-Wu
YW
Molkentin
Jeffery D
JD
Erlinge
David
D
Gomez
Maria F
MF
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000502:physiology; D020013:Calcium Signaling; D002536:Cerebral Arteries / Q000166:cytology / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058473:Receptors, Purinergic P2Y2; D015533:Transcriptional Activation / Q000187:drug effects; D014530:Uridine Diphosphate / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
C494244:A 285222; D050778:NFATC Transcription Factors; C546386:P2ry2 protein, mouse; D011720:Pyrazoles; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate; D005947:Glucose; D014544:Uridine Triphosphate