2001 Fiscal Year Annual Research Report

動脈硬化症特に糖尿病大血管障害の病態におけるVEGFの役割と抗VEGF療法の効果

Research Project

Project/Area Number	12770632
Research Institution	University of Tsukuba
Principal Investigator	曽根博仁筑波大学, 臨床医学系, 講師 (30312846)
Keywords	血管内皮増殖因子(VEGF) / 糖尿病合併症 / 血管内皮細胞 / 糖輸送担体1(GLUT1) / MAPK / 慢性関節リウマチ / ERK
Research Abstract	血管内皮増殖因子(VEGF)は糖尿病網膜症(DR)の血管新生・浸出性病変の発症・進展に主要な役割を果たす。一方、高血糖による血管内皮細胞障害の第一段階として、多量の血中グルコース(Glu)が同細胞内に取込まれることが重要である。同細胞のGlu取込みは専ら糖輸送担体1(GLUT1)により行われるため、GLUT1発現量は細胞内Glu取込み量を規定する重要因子である。そこでDRの病態におけるVEGFとGLUT1の、血管内皮細胞への相互作用について検討した。培養ウシ網膜血管内皮細胞(BREC)の培地中にVEGFを添加した際の、細胞内へのGlu取込みとGLUT1の発現を検討した。次に血管内皮由来のGLUT1安定強発現細胞株を作成し、そのMAPK活性について検討した。BRECにおいて、VEGF用量依存的にGlu取込みの有意な上昇(VEGF濃度50ng/mlにおいて1.6倍)を認めた。その機序として、VEGFがPKC-β1を介してGLUT1を細胞表面にtranslocateさせていることが示唆された。またGLUT1強発現細胞において、活性型ERK(p42/44 MAPK)は有意に上昇(1.8倍)していることが明らかになった。他のMAPKファミリーであるJNK,p38活性の上昇は認めなかった。ERKは強力な細胞増殖シグナルであることから、VEGFは、GLUT1を介してERKを活性化する機序を通じて、DR増悪に関与していることが示唆された。その他、今回の結果を応用して、VEGFの自己免疫疾患における関与も検討し、本因子が、慢性関節リウマチの発症・進展に深く関与していることなどを、動物モデルおよび臨床検体を用いた検討にて示した。

Research Products

(14 results)

All Other

All Publications (14 results)

[Publications] Sone H.: "Enhancement of Glucose Transport by Vascular Endothelial Growth Factor in Retinal Endothelial Cells"Invest. Ophthalmol. Vis. Sci.. 41. 1876-1884 (2000)
[Publications] Sone H.: "Elevated levels of vascular endothelial growth factor in the sera of patients with rheumatoid arthritis : Correlation with disease activity"Life Sci.. 69. 1861-1869 (2001)
[Publications] Sone H.: "Neutralization of vascular endothelial growth factor prevents collagen-induced arthritis and ameliorates established disease in mice. Biochemical and Biophysical Research Communications"Biochem Biophys Res Commun. 281・2. 562-568 (2001)
[Publications] Sone H.: "Ibuprofen-Related Hypoglycemia in a Patient Receiving Sulfonylurea"Ann Intern Med. 134・4. 344 (2001)
[Publications] Ishiguchi T.: "Gastric distension-induced pyloric relaxation : central nervous system regulation and effects of acute hyperglycaemia in the rat"J Physiol. 15・533. 801-813 (2001)
[Publications] Sone H.: "Animal models of hyperinsulinemia and insulin resistance. Part A : Transgenic Models disrupting insulin signaling and action"Trend Mol Med. 7. 320-322 (2001)
[Publications] Sone H.: "Animal models of hyperinsulinemia and insulin resistance. Part B : Polygenic and other animal models"Trend Mol Med. 7. 373-376 (2001)
[Publications] Sakakura Y.: "Sterol Regulatory Element-Binding Proteins Induce an Entire Pathway of Cholesterol Synthesis"Biochem Biophys Res Commun. 286・1. 176-183 (2001)
[Publications] Hasty A.H.: "Severe hypercholesterolemia, hypertriglyceridemia, and atherosclerosis in mice lacking both leptin and the low density lipoprotein receptor"J Biol Chem. 276. 37402-37408 (2001)
[Publications] Iida K.T.: "Insulin up-regulates tumor necrosis factor-alpha production in macrophages through an extracellular-regulated kinase-dependent pathway"J Biol Chem. 276. 32531-32537 (2001)
[Publications] Sone H.: "Acetyl-coenzyme A synthetase is a lipogenic enzyme controlled by SREBP-1 and energy status"Am J Physiol. 282. E222-E230 (2002)
[Publications] Matsuzaka T.: "Dual regulation of mouse delta-5 and -6 desaturase gene expression by SREBP-1 and PPAR alpha"J Lipid Res. 43. 107-114 (2002)
[Publications] Yoshikawa T.: "Polyunsaturated fatty acids suppress sterol regulatory element-binding protein-1c promoter activity by inhibition of liver X receptor (LXR) binding to LXR response elements"J Biol Chem. 277. 1705-1711 (2002)
[Publications] Okuda Y.: "Acute gliclazide administration enhances glucose and ketone body utilization in the perfused normal and streptzotocin diabetic rats hind limb"Life Sci. (印刷中).

2001 Fiscal Year Annual Research Report

動脈硬化症特に糖尿病大血管障害の病態におけるVEGFの役割と抗VEGF療法の効果

Principal Investigator

曽根 博仁 筑波大学, 臨床医学系, 講師 (30312846)

Research Products

[Publications] Sone H.: "Enhancement of Glucose Transport by Vascular Endothelial Growth Factor in Retinal Endothelial Cells"Invest. Ophthalmol. Vis. Sci.. 41. 1876-1884 (2000)

[Publications] Sone H.: "Elevated levels of vascular endothelial growth factor in the sera of patients with rheumatoid arthritis : Correlation with disease activity"Life Sci.. 69. 1861-1869 (2001)

[Publications] Sone H.: "Neutralization of vascular endothelial growth factor prevents collagen-induced arthritis and ameliorates established disease in mice. Biochemical and Biophysical Research Communications"Biochem Biophys Res Commun. 281・2. 562-568 (2001)

[Publications] Sone H.: "Ibuprofen-Related Hypoglycemia in a Patient Receiving Sulfonylurea"Ann Intern Med. 134・4. 344 (2001)

[Publications] Ishiguchi T.: "Gastric distension-induced pyloric relaxation : central nervous system regulation and effects of acute hyperglycaemia in the rat"J Physiol. 15・533. 801-813 (2001)

[Publications] Sone H.: "Animal models of hyperinsulinemia and insulin resistance. Part A : Transgenic Models disrupting insulin signaling and action"Trend Mol Med. 7. 320-322 (2001)

[Publications] Sone H.: "Animal models of hyperinsulinemia and insulin resistance. Part B : Polygenic and other animal models"Trend Mol Med. 7. 373-376 (2001)

[Publications] Sakakura Y.: "Sterol Regulatory Element-Binding Proteins Induce an Entire Pathway of Cholesterol Synthesis"Biochem Biophys Res Commun. 286・1. 176-183 (2001)

[Publications] Hasty A.H.: "Severe hypercholesterolemia, hypertriglyceridemia, and atherosclerosis in mice lacking both leptin and the low density lipoprotein receptor"J Biol Chem. 276. 37402-37408 (2001)

[Publications] Iida K.T.: "Insulin up-regulates tumor necrosis factor-alpha production in macrophages through an extracellular-regulated kinase-dependent pathway"J Biol Chem. 276. 32531-32537 (2001)

[Publications] Sone H.: "Acetyl-coenzyme A synthetase is a lipogenic enzyme controlled by SREBP-1 and energy status"Am J Physiol. 282. E222-E230 (2002)

[Publications] Matsuzaka T.: "Dual regulation of mouse delta-5 and -6 desaturase gene expression by SREBP-1 and PPAR alpha"J Lipid Res. 43. 107-114 (2002)

[Publications] Yoshikawa T.: "Polyunsaturated fatty acids suppress sterol regulatory element-binding protein-1c promoter activity by inhibition of liver X receptor (LXR) binding to LXR response elements"J Biol Chem. 277. 1705-1711 (2002)

[Publications] Okuda Y.: "Acute gliclazide administration enhances glucose and ketone body utilization in the perfused normal and streptzotocin diabetic rats hind limb"Life Sci. (印刷中).

曽根博仁筑波大学, 臨床医学系, 講師 (30312846)