A role of capillary endothelial cells in pathophysiology of sepsis ; basic study by using endothelial-specific PPAR. knockout mice

2011 Fiscal Year Final Research Report

• Project/Area Number: 21592303
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Emergency medicine
• Research Institution: Gunma University
• Principal Investigator: KUNIMOTO Fumio 群馬大学, 医学部, 准教授 (70125847)
• Co-Investigator(Kenkyū-buntansha): ISO Tatsuya 群馬大学, 医学部, 助教 (10400756)
• Project Period (FY): 2009 – 2011
• Keywords: 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

Research Abstract

We hypothesized that insulin-resistance and metabolic failure under sepsis could be attributable to capillary-endothelial failure. We found that PPARγ, a nuclear receptor for metabolic regulation, is abundantly expressed in capillary endothelial cells and induces its target genes such as FABP4 and FAT/CD36. However, there was no significant difference regarding survival rate between wild type and PPARγ-endothelial knockout mice after LPS treatment, or sepsis model. In contrast, survival rate of FABP4/5 double knockout mice was higher than wild type after LPS treatment.

Research Products

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