Nuclear factor of activated T cells regulates osteopontin expression in arterial smooth muscle in response to diabetes-induced hyperglycemia.
OBJECTIVE
Hyperglycemia is a recognized risk factor for cardiovascular disease in diabetes. Recently, we reported that high glucose activates the Ca(2+)/calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT) in arteries ex vivo. Here, we sought to determine whether hyperglycemia activates NFAT in vivo and whether this leads to vascular complications.


RESULTS
An intraperitoneal glucose-tolerance test in mice increased NFATc3 nuclear accumulation in vascular smooth muscle. Streptozotocin-induced diabetes resulted in increased NFATc3 transcriptional activity in arteries of NFAT-luciferase transgenic mice. Two NFAT-responsive sequences in the osteopontin (OPN) promoter were identified. This proinflammatory cytokine has been shown to exacerbate atherosclerosis and restenosis. Activation of NFAT resulted in increased OPN mRNA and protein in native arteries. Glucose-induced OPN expression was prevented by the ectonucleotidase apyrase, suggesting a mechanism involving the release of extracellular nucleotides. The calcineurin inhibitor cyclosporin A or the novel NFAT blocker A-285222 prevented glucose-induced OPN expression. Furthermore, diabetes resulted in higher OPN expression, which was significantly decreased by in vivo treatment with A-285222 for 4 weeks or prevented in arteries from NFATc3(-/-) mice.


CONCLUSIONS
These results identify a glucose-sensitive transcription pathway in vivo, revealing a novel molecular mechanism that may underlie vascular complications of diabetes.
Nilsson-Berglund
Lisa M
LM
Department of Clinical Sciences in Malmö, Lund University, Malmö, Sweden.
Zetterqvist
Anna V
AV
Nilsson-Ohman
Jenny
J
Sigvardsson
Mikael
M
González Bosc
Laura V
LV
Smith
Maj-Lis
ML
Salehi
Albert
A
Agardh
Elisabet
E
Fredrikson
Gunilla Nordin
GN
Agardh
Carl-David
CD
Nilsson
Jan
J
Wamhoff
Brian R
BR
Hultgårdh-Nilsson
Anna
A
Gomez
Maria F
MF
D000818:Animals; D001081:Apyrase / Q000494:pharmacology; D001158:Arteries / Q000378:metabolism; D001665:Binding Sites; D001786:Blood Glucose / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053495:Osteopontin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D014544:Uridine Triphosphate / Q000378:metabolism
C494244:A 285222; D001786:Blood Glucose; D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D050778:NFATC Transcription Factors; C494009:Nfatc3 protein, mouse; D011720:Pyrazoles; D012333:RNA, Messenger; C506896:Spp1 protein, mouse; D053495:Osteopontin; D016572:Cyclosporine; D019703:Calcineurin; D001081:Apyrase; D014544:Uridine Triphosphate