PPARガンマKOマウスを用いた敗血症モデル毛細血管内皮細胞の果たす役割の検討

2011 年度 研究成果報告書

• 研究課題/領域番号: 21592303
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 救急医学
• 研究機関: 群馬大学
• 研究代表者: 國元 文生 群馬大学, 医学部, 准教授 (70125847)
• 研究分担者: 磯 達也 群馬大学, 医学部, 助教 (10400756)
• 研究期間 (年度): 2009 – 2011
• キーワード: 敗血症 / 毛細血管内皮細胞 / 脂肪酸代謝 / 糖代謝 / 心機能 / PPARγ / FABP4 / FABP5

研究概要

敗血症の際のインスリン抵抗性や代謝不全は、毛細血管機能不全が一因を担うと考えた。代謝制御因子PPARγは毛細血管内皮細胞に豊富に発現し、標的遺伝子であるFABP4・FAT/CD36を誘導する。PPARγの血管内皮特異的ノックアウトマウスを用いた敗血症モデルでは、野生型と比較して生命予後に差異を認めなかった。FABP4/5ダブルノックアウトマウスを用いた敗血症モデルでは、野生型と比較して生命予後が改善した。

研究成果

• [雑誌論文] Stearoyl-CoA Desaturase-1 (SCD1) Augments Saturated Fatty Acid-Induced Lipid Accumulation and Inhibits Apoptosis in Cardiac Myocytes (2012)
  • 著者名/発表者名: Matsui H, Yokoyama T, Sekiguchi K, Iijima D, Sunaga H, Maniwa M, Ueno M, Iso T, Arai M, Kurabayashi M.
  • 雑誌名: PLoS One 巻: 7(3)
  • 査読あり
• [雑誌論文] Compound and digenic heterozygosity in desmosome genes as a cause of arrhythmogenic right ventricular cardiomyopathy in Japanese patients (2012)
  • 著者名/発表者名: Nakajima T, Kaneko Y, Irie T, Takahashi R, Kato T, Iijima T, Iso T, Kurabayashi M.
  • 雑誌名: Circ J 巻: 76(3) ページ: 737-43
  • 査読あり
• [雑誌論文] Marked lipomatous hypertrophy of the right ventricular wall : a distinct clinicopathological entity from arrhythmogenic right ventricular cardiomyopathy (2012)
  • 著者名/発表者名: Nakajima T, Kaneko Y, Fukuda N, Irie T, Iso T, Kurabayashi M
  • 雑誌名: Int J Cardiol 巻: 154(3) ページ: 379-80
  • 査読あり
• [雑誌論文] Runx2/Smad3 complex negatively regulates TGF-β-induced connective tissue growth factor gene expression in vascular smooth muscle cells (2012)
  • 著者名/発表者名: Ohyama Y, Tanaka T, Shimizu T, Matsui H, Sato H, Koitabashi N, Doi H, Iso T, Arai M, Kurabayashi M.
  • 雑誌名: J Atheroscler Thromb 巻: 19(1) ページ: 23-35
  • 査読あり
• [雑誌論文] 筋型毛細血管内皮細胞を介する脂肪酸代謝のメカニズム (2011)
  • 著者名/発表者名: 磯達也, 倉林正彦
  • 雑誌名: 医学のあゆみ 巻: 238 ページ: 198-199
• [雑誌論文] 筋型毛細血管内皮細胞を介する脂肪酸代謝のメカニズム (2011)
  • 著者名/発表者名: 磯達也, 倉林正彦
  • 雑誌名: Therapeutic Research 巻: 32 ページ: 739-743
• [雑誌論文] Notch Induces Myofibroblast Differentiation of Alveolar Epithelial Cells via TGFb/Smad3 Pathway (2011)
  • 著者名/発表者名: Aoyagi-Ikeda K, Maeno T, Matsui H, Ueno M, Hara K, Aoki Y, Aoki F, Shimizu T, Doi H, Kawai-Kowase K, Iso T, Suga T, Arai M, Kurabayashi M.
  • 雑誌名: Am J Respir Cell Mol Biol 巻: 45(1) ページ: 136-44
  • 査読あり
• [雑誌論文] Activation of receptor for advanced glycation end products induces osteogenic differentiation of vascular smooth muscle cells (2011)
  • 著者名/発表者名: Suga T, Iso T, Shimizu T, Tanaka T, Yamagishi S, Takeuchi M, Imaizumi T, Kurabayashi M.
  • 雑誌名: J Atheroscler Thromb 巻: 18(8) ページ: 670-83
  • 査読あり
• [雑誌論文] Notch signaling pathway enhances bone morphogenetic protein 2 (BMP2) responsiveness of Msx2 gene to induce osteogenic differentiation and mineralization of vascular smooth muscle cells (2011)
  • 著者名/発表者名: Shimizu T, Tanaka T, Iso T, Matsui H, Ooyama Y, Kawai-Kowase K, Arai M, Kurabayashi M.
  • 雑誌名: J Biol Chem 巻: 286(21) ページ: 19138-48
  • 査読あり
• [雑誌論文] Identification of Six Novel SCN5A Mutations in Japanese Patients with Brugada Syndrome (2011)
  • 著者名/発表者名: Nakajima T, Kaneko Y, Saito A, Irie T, Tange S, Iso T, Kurabayashi M.
  • 雑誌名: Int Heart J 巻: 52(1) ページ: 27-31
  • 査読あり
• [雑誌論文] Multiple Spontaneous Coronary Artery Ruptures and Cardiac Tamponade in Vascular Ehlers-Danlos Syndrome (2011)
  • 著者名/発表者名: Yoshiaki Ohyama, Tatsuya Iso, Adriana Carolina Vargas Nino, Masaru Obokata, Rieko Takahashi, Wataru Okumura, Akihiko Nakano, Masao Amano, Isao Naito, Masamitsu Takatama, Masahiko Kurabayashi
  • 雑誌名: Journal of Cardiology Cases 2010 巻: 3 ページ: 29-32
  • 査読あり
• [雑誌論文] Post myocardial ischemia-associated torsades de pointes in a patient carrying a KCNQ1 G643S variant (2010)
  • 著者名/発表者名: Nakajima T, Kaneko Y, Saito A, Irie T, Kato T, Iso T, Kurabayashi M.
  • 雑誌名: Intern Med 巻: 49(23) ページ: 2587-91
  • 査読あり
• [雑誌論文] Aborted cardiac arrest in a patient carrying KCNE1 D85N variant during the postpartum period (2010)
  • 著者名/発表者名: Nakajima T, Kaneko Y, Manita M, Iso T, Kurabayashi M.
  • 雑誌名: Intern Med 巻: 49(17) ページ: 1875-8
  • 査読あり
• [雑誌論文] Fibroblast Growth Factor 2 Induces Osteogenic Differentiation through a Runx2 Activation in Vascular Smooth Muscle Cells (2010)
  • 著者名/発表者名: Nakahara T, Sato H, Shimizu T, Tanaka T, Matsui H, Kawai-Kowase K, Sato M, Iso T, Arai M, Kurabayashi M.
  • 雑誌名: Biochem Biophys Res Commun 巻: 394(2) ページ: 243-8
  • 査読あり
• [雑誌論文] Marked high density lipoprotein deficiency due to apolipoprotein A-I Tomioka (codon 138 deletion) (2009)
  • 著者名/発表者名: Wada M, Iso T, Asztalos BF, Takama N, Nakajima T, Seta Y, Kaneko K, Taniguchi Y, Kobayashi H, Nakajima K, Schaefer EJ, Kurabayashi M.
  • 雑誌名: Atherosclerosis 巻: 207(1) ページ: 157-161
  • 査読あり
• [雑誌論文] Notch signaling induces osteogenic differentiation and mineralization of vascular smooth muscle cells : role of Msx2 gene induction via Notch-RBP-Jk signaling (2009)
  • 著者名/発表者名: Shimizu T, Tanaka T, Iso T, Doi H, Sato H, Kawai-Kowase K, Arai M, Kurabayashi M.
  • 雑誌名: Arterioscler Thromb Vasc Biol 巻: 29(7) ページ: 1104-11
  • 査読あり
• [雑誌論文] Notch signaling regulates the differentiation of bone marrow-derived cells into smooth muscle-like cells during arterial lesion formation (2009)
  • 著者名/発表者名: Doi H, Iso T, Shiba Y, Sato H, Yamazaki M, Oyama Y, Akiyama H, Tanaka T, Tomita T, Arai M, Takahashi M, Ikeda U, Kurabayashi M.
  • 雑誌名: Biochem Biophys Res Commun 巻: 381 ページ: 654-659
  • 査読あり
• [学会発表] Replacement Injection Methods can Reliably Visualize the Right Heart (2012)
  • 著者名/発表者名: Takehiro Nakahara, Nogiku Niwamae, Norimichi Koitabashi, Ryoutarou Seki, Tadashi Nakajima , Tatsuya Iso, Yuichiro Saitoh, Yoshiaki Kaneko, Masashi Arai, Yoshito Tsushima, Masahiko Kurabayashi
  • 学会等名: The 76th Annual Scientific Meeting of the Japanese Circulation Society
  • 発表場所: Fukuoka
  • 年月日: 2012-03-18
• [学会発表] PPARγ Expressed in Capillary Endothelial Cells Regulates Trans-endothelial Fatty Acid Transport in the Heart via an Induction of FABP4 (2012)
  • 著者名/発表者名: Kosaku Goto, Tatsuya Iso, Hirofumi Hanaoka, Aiko Yamaguchi, Toshihiro Suga, Hiroki Matsui, Masashi Arai, Keigo Endo, Frank Gonzalez, Masahiko Kurabayashi
  • 学会等名: The 76th Annual Scientific Meeting of the Japanese Circulation Society
  • 発表場所: Fukuoka
  • 年月日: 2012-03-17
• [学会発表] Compound and Digenic Heterozygosity in Desmosome Genes as a Cause of Arrhythmogenic Right Ventricular Cardiomyopathy in Japanese Patients (2012)
  • 著者名/発表者名: Tadashi Nakajima, Yoshiaki Kaneko, Tadanobu Irie, Rieko Takahashi, Toshimitsu Kato, Takafumi Iijima, Tatsuya Iso, Masahiko Kurabayashi
  • 学会等名: The 76th Annual Scientific Meeting of the Japanese Circulation Society
  • 発表場所: Fukuoka
  • 年月日: 2012-03-17
• [学会発表] Masahiko Kurabayashi Fatty Acid Binding Protein 4 is induced by Notch Signaling via Induction of PPARγ in Capillary Endothelial Cells in Heart (2012)
  • 著者名/発表者名: Tatsuya Iso, Naoto Yajima , Kyosuke Takeshita, Hiroki Matsui, Kosaku Goto, Tomoyuki Yokoyama
  • 学会等名: The 76th Annual Scientific Meeting of the Japanese Circulation Society
  • 発表場所: Fukuoka
  • 年月日: 2012-03-17
• [学会発表] Fatty Acid Translocase (FAT/CD36) is Transcriptionally Regulated by PPARγ in Capillary Endothelial Cells in Heart (2012)
  • 著者名/発表者名: Kosaku Goto, Tatsuya Iso, Akinari Hattori , Naoto Yajima, Hiroki Matsui, Tomoyuki Yokoyama, Masashi Arai, Masahiko Kurabayashi
  • 学会等名: The 76th Annual Scientific Meeting of the Japanese Circulation Society
  • 発表場所: Fukuoka
  • 年月日: 2012-03-17
• [学会発表] Long-Chain Fatty Acid Elongase, Elovl6, is Crucial for Vascular Smooth Muscle Cell Proliferation Underlying Neointimal Hyperplasia (2012)
  • 著者名/発表者名: Hiroaki Sunaga, Hiroki Matsui, Tatsuya Iso, Masahiko Kurabayashi, Tomoyuki Yokoyama
  • 学会等名: The 76th Annual Scientific Meeting of the Japanese Circulation Society
  • 発表場所: Fukuoka
  • 年月日: 2012-03-16
• [学会発表] Physiological cardiac hypertrophy is evoked by markedly increased glucose consumption and insulin signaling in mice lacking both fatty acid binding protein 4 and-5 (2011)
  • 著者名/発表者名: Tatsuya Iso, Kazuhisa Maeda, Kosaku Goto, Hiroki Matsui, Masashi Arai, Gokhan S. Hotamisligil, Masahiko Kurabayashi
  • 学会等名: Annual meeting of American Heart Association
  • 発表場所: Orland, USA
  • 年月日: 2011-11-14
• [学会発表] Peroxisome Proliferator Activated Receptor-Alpha (PPAR-・) Regulates Trans-endothelial Fatty Acid Transport in Capillary Endothelial Cells (2011)
  • 著者名/発表者名: Tatsuya Iso, Yasunori Irie, Yuji Shinagawa, Hiroki Matsui, Kosaku Goto, Tomoyuki Yokoyama, Masahiko Kurabayashi
  • 学会等名: Functional Similarity between PPAR-・ and PPAR-・・ Annual meeting of American Heart Association
  • 発表場所: Orland, USA
  • 年月日: 2011-11-14
• [学会発表] Peroxisome Proliferator Activated Receptor Gamma Regulates Trans-endothelial Fatty Acid Transport via Induction of Fatty Acid Binding Protein 4 and Fatty Acid Translocase in Capillary Endothelial Cells in Heart and Adiose Tissue (2010)
  • 著者名/発表者名: Kosaku Goto, Tatsuya Iso, Hirofumi Hanaoka, Toshihiro Suga, Hiroki Matsui, Masashi Arai, Keigo Endo, Frank J Gonzalez, Masahiko Kurabayashi
  • 学会等名: Annual meeting of American Heart Association
  • 発表場所: Chicago, USA
  • 年月日: 2010-11-17
• [学会発表] Notch signaling enhances BMP2-induced osteogenic differentiation of vascular smooth muscle cells and vascular calcification (2010)
  • 著者名/発表者名: Shimizu T., Tanaka T., Iso T., Kurabayashi M.
  • 学会等名: XX^<th> World Congress International Society for Heart Research (ISHR)
  • 発表場所: Kyoto
  • 年月日: 2010-05-16
• [学会発表] Elevated stearoyl-CoA desaturase-1 expression in obese and diabetic heart plays a protective role against fatty acid-induced cardiac dysfunction (2010)
  • 著者名/発表者名: Matsui H., Yokoyama T., Iijima D., Maniwa M., Iso T., Arai M., Kurabayashi M
  • 学会等名: XX^<th> World Congress International Society for Heart Research (ISHR)
  • 発表場所: Kyoto
  • 年月日: 2010-05-16
• [学会発表] Notch-peroxisome proliferator activated receptor-gamma2 pathway regulates transendothelial fatty acid transport in capillary endothelial cells in heart (2010)
  • 著者名/発表者名: Goto K., Iso T., Suga T., Matsui H., Arai M., Kurabayashi M.
  • 学会等名: XX^<th> World Congress International Society for Heart Research (ISHR)
  • 発表場所: Kyoto
  • 年月日: 2010-05-16
• [学会発表] A possible role of transendothelial glycerol transport through aquaporin 7 regulated by peroxisome proliferated activator reveptor-gamma (2010)
  • 著者名/発表者名: Haque A., Iso T.,Kunimoto F.,Saito S.,Kurabayashi M.
  • 学会等名: XX^<th> World Congress International Society for Heart Research (ISHR)
  • 発表場所: Kyoto
  • 年月日: 2010-05-16
• [学会発表] Muscle-type capillary endothelial cells actively transport fatty acids via intracellular fatty acid binding protein-4 and-5 (2010)
  • 著者名/発表者名: Iso T., Maeda K., Hanaoka H., Suga T., Matsui H., Goto K., Arai M., Endo K., Gokhan H., Kurabayashi M.
  • 学会等名: XX^<th> World Congress International Society for Heart Research (ISHR)
  • 発表場所: Kyoto
  • 年月日: 2010-05-14
• [学会発表] Runx2 suppresses atrial and B-type natriuretic peptide gene expression in rat cardiac myocytes (2010)
  • 著者名/発表者名: Nakahara T., Shimizu T., Tanaka T., Kowase K., Iso T., Arai M., Kurabayashi M.
  • 学会等名: XX^<th> World Congress International Society for Heart Research (ISHR)
  • 発表場所: Kyoto
  • 年月日: 2010-05-13
• [学会発表] Steroyl-CoA desaturase-1 has a protective effect against saturated fatty acids-induced osteogenic differentiation and apoptosis in vascular smooth muscle cells (2010)
  • 著者名/発表者名: Matsui H., Yokoyama T., Gotoh Y., Iso T., Arai M., Kurabayashi M.
  • 学会等名: XX^<th> World Congress International Society for Heart Research (ISHR)
  • 発表場所: Kyoto
  • 年月日: 2010-05-13
• [学会発表] Runx2 Inhibits TGF・-induced Connective Tissue Growth Factor Gene Expression Through Physical Association with Smad3 in Vascular Smooth Muscle Cells (2009)
  • 著者名/発表者名: Yoshiaki Oyama, Toru Tanaka, Takehisa Shimizu, Hiroko Sato, Norimichi Koitabashi, Hiroshi Doi, Tatsuya Iso, Masashi Arai, Masahiko Kurabayashi
  • 学会等名: Annual meeting of American Heart Association
  • 発表場所: Orland, USA
  • 年月日: 2009-11-18
• [学会発表] Notch-Peroxisome Proliferator Activated Receptor Gamma2 Pathway Regulates Transendothelial Fatty Acid Transport via Induction of Fatty Acid Binding Protein 4 and Fatty Acid Translocase in Capillary Endothelial Cells in Heart (2009)
  • 著者名/発表者名: Kosaku Goto, Tatsuya Iso, Toshihiro Suga, Hiroki Matsui, Masashi Arai, Frank J Gonzalez, Masahiko Kurabayashi
  • 学会等名: Annual meeting of American Heart Association
  • 発表場所: Orland, USA
  • 年月日: 2009-11-17
• [学会発表] Bone Morphogenetic Protein-2 (BMP-2) and BMP-7 Act as Instructive Factors to Specify Notch Signaling Controlling Smooth Muscle Cell Phenotype (2009)
  • 著者名/発表者名: Takehisa Shimizu, Toru Tanaka, Tatsuya Iso, Keiko Kawai-Kowase, Masahiko Kurabayashi
  • 学会等名: Annual meeting of American Heart Association
  • 発表場所: Orland, USA
  • 年月日: 2009-11-17
• [学会発表] Muscle-Type Capillary Endothelial Cells Actively Transport Fatty Acids via Intracellular Fatty Acid Binding Protein-4 and-5 (2009)
  • 著者名/発表者名: Tatsuya Iso, Kazuhisa Maeda, Hirofumi Hanaoka, Toshihiro Suga, Hiroki Matsui, Kosaku Goto, Masashi Arai, Keigo Endo, Gohkan Hotamisligil, Masahiko Kurabayashi
  • 学会等名: Annual meeting of American Heart Association
  • 発表場所: Orland, USA
  • 年月日: 2009-11-16
• [学会発表] Increased Stearoyl-CoA Desaturase-1 Expression in Obese and Diabetic Heart Plays a Protective Role Against Fatty Acid-Induced Cardiac Dysfunction (2009)
  • 著者名/発表者名: Hiroki Matsui, Tomoyuki Yokoyama, Daisuke Iijima, Kenichi Sekiguchi, Tatsuya Iso, Masahi Arai, Masahiko Kurabayashi
  • 学会等名: Annual meeting of American Heart Association
  • 発表場所: Orland, USA
  • 年月日: 2009-11-16
• [学会発表] Serum RAGE ligands induce osteoblastic differentiation of vascular smooth muscle cells via RAGE-Notch-Msx2 pathway (2009)
  • 著者名/発表者名: Toshihiro Suga, Tatsuya Iso, Takehisa Shimizu, Toru Tanaka, Sho-ichi Yamagishi, Masashi Arai, Tsutomu Imaizumi, Masahiko Kurabayash
  • 学会等名: 10^<th> international symposium on mechanism of vasodilatation
  • 発表場所: Matsushima, Japan
  • 年月日: 2009-06-01
• [学会発表] Capillary-Specific Expression of FABP4 and FABP5 (Fatty Acid Binding Proteins): A Possible Role of Fatty Acid Transport through Capillary Endothelium (2009)
  • 著者名/発表者名: Tatsuya Iso, Hiroki Matsui, Toshihiro Suga, Toru Tanaka, Masashi Arai, Masahiko Kurabayashi
  • 学会等名: 10^<th> international symposium on mechanism of vasodilatation
  • 発表場所: Matsushima, Japan
  • 年月日: 2009-06-01
• [図書] 第4章シグナル伝達「Notchシグナル」、血管生物医学事典 (2011)
  • 著者名/発表者名: 磯達也
  • 総ページ数: 266-268
  • 出版者: 朝倉書店
• [図書] 第5章転写因子「Hey」、血管生物医学事典
  • 著者名/発表者名: 磯達也
  • 総ページ数: 399-400
  • 出版者: 朝倉書店