Nuclear Factor of Activated T Cells Regulates Osteopontin Expression in Arterial Smooth Muscle in Response to Diabetes-Induced Hyperglycemia.

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Nuclear Factor of Activated T Cells Regulates Osteopontin Expression in Arterial Smooth Muscle in Response to Diabetes-Induced Hyperglycemia. / Berglund, Lisa; Zetterqvist, Anna; Öhman, Jenny; Sigvardsson, Mikael; González Bosc, Laura V; Smith, Maj-Lis; Salehi, S Albert; Agardh, Elisabet; Nordin Fredrikson, Gunilla; Agardh, Carl-David; Nilsson, Jan; Wamhoff, Brian R; Hultgårdh, Anna; Gomez, Maria.

I: Arteriosclerosis, Thrombosis and Vascular Biology, Vol. 30, 2010, s. 218-U154.

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T1 - Nuclear Factor of Activated T Cells Regulates Osteopontin Expression in Arterial Smooth Muscle in Response to Diabetes-Induced Hyperglycemia.

AU - Berglund, Lisa

AU - Zetterqvist, Anna

AU - Öhman, Jenny

AU - Sigvardsson, Mikael

AU - González Bosc, Laura V

AU - Smith, Maj-Lis

AU - Salehi, S Albert

AU - Agardh, Elisabet

AU - Nordin Fredrikson, Gunilla

AU - Agardh, Carl-David

AU - Nilsson, Jan

AU - Wamhoff, Brian R

AU - Hultgårdh, Anna

AU - Gomez, Maria

N1 - The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Department of Clinical Sciences, Malmö (013240000), Experimental Cardiovascular Research Unit (013242110), Stem Cell Center (013041110), Vessel Wall Biology (013212028), Islet cell physiology (013212142), Unit on Vascular Diabetic Complications (013241510)

PY - 2010

Y1 - 2010

N2 - 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. METHODS AND 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.

AB - 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. METHODS AND 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.

U2 - 10.1161/ATVBAHA.109.199299

DO - 10.1161/ATVBAHA.109.199299

M3 - Article

VL - 30

SP - 218-U154

JO - Arteriosclerosis, Thrombosis and Vascular Biology

T2 - Arteriosclerosis, Thrombosis and Vascular Biology

JF - Arteriosclerosis, Thrombosis and Vascular Biology

SN - 1524-4636

ER -