Studies on Molecular-Cellular Mechanisms of Protein C Anticoagulant Pathway Crucial for Life Homeostasis

• Project/Area Number: 21390292
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Suzuka University of Medical Science (2011); Mie University (2009-2010)
• Principal Investigator: SUZUKI Koji 鈴鹿医療科学大学, 薬学部, 教授 (70077808)
• Co-Investigator(Kenkyū-buntansha): DEYASHIKI Yoshihiro 鈴鹿医療科学大学, 薬学部, 教授 (00202193) ; HAYASHI Tatsuya 三重県立看護大学, 教授 (00242959) ; OKAMOTO Takayuki 三重大学, 医学系研究科, 助教授 (30378286)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2011: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2010: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2009: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: プロテインC / プロテインS / トロンボモジュリン / C4b結合タンパク質 / 血管内皮細胞 / 細胞間ギャップ結合 / コネキシン32 / 血栓症 / C4b結合蛋白質 / Protein C / 血液凝固反応 / 組織因子 / ギャップ結合 / コネキシン / 炎症 / 血小板

Research Abstract

We studied the molecular-cellular mechanism of anticoagulant protein C pathway which is crucial for life homeostasis. The results obtained in the research are as follows. (1) Lipopolysaccharide-Toll-like receptor-mediated signaling regulates expression of protein S and C4b-binding protein in the liver. (2) The multi-functional serine protease inhibitor, protein C inhibitor regulates many organ functions beyond thrombosis and hemostasis. (3) Cellular gap junction molecule, connexin32 protects against vascular inflammation by modulating inflammatory cytokine expression by endothelial cells.

Research Products

• [Journal Article] Thrombomodulin, a bi-functional modulator of inflammation and coagulation in sepsis (2011)
  • Author(s): Okamoto T, Suzuki K, et al
  • Journal Title: Crit Care Res Pract Volume: 2012 Pages: 10-10
  • DOI: 10.1155/2012/614545
  • Peer Reviewed
• [Journal Article] Connexin32 protects against vascular inflammation by modulating inflammatory cytokine expression by endothelial cells (2011)
  • Author(s): Okamoto T, Suzuki K, et al
  • Journal Title: Exp Cell Res Pages: 348-355
  • Peer Reviewed
• [Journal Article] Impairment of protein C secretion in protein C-deficient patients carrying an Asp297 mutation (2011)
  • Author(s): Yamanouchi J, Suzuki K, et al
  • Journal Title: Int J Hematol Volume: 94巻 Pages: 213-215
  • NAID: 10029537247
  • Peer Reviewed
• [Journal Article] Effect of a prostaglandin I(2) analog on the expression of thrombomodulin in liver and spleen endothelial cells after an extensive hepatectomy (2011)
  • Author(s): Usui M, Suzuki K, et al
  • Journal Title: Surg Today Volume: 41巻 Pages: 230-236
  • Peer Reviewed
• [Journal Article] 血栓症を発症した複合ヘテロ接合体性プロテインC欠乏症患者で認められた2種の遺伝子変異とそれぞれのプロテインC産生に及ぼす影響 (2011)
  • Author(s): 油井知雄、鈴木宏治, 他
  • Journal Title: 日本血栓止血学会雑誌 Volume: 22巻 Pages: 87-99
  • NAID: 10031162927
  • Peer Reviewed
• [Journal Article] 私の血栓止血研究-事始め- (2011)
  • Author(s): 鈴木宏治
  • Journal Title: 日本血栓止血学会雑誌 Volume: 22巻 Pages: 202-212
  • NAID: 10031162945
• [Journal Article] 凝固線溶系-凝固系の最新の進歩- (2011)
  • Author(s): 鈴木宏治
  • Journal Title: Thrombosis Medicine Volume: 1巻 Pages: 13-20
• [Journal Article] プロテインCとプロテインS (2011)
  • Author(s): 鈴木宏治
  • Journal Title: Thrombosis Medicine Volume: 1巻 Pages: 94-97
• [Journal Article] トロンボモジュリンを介した凝固炎症反応と敗血症性DIC (2011)
  • Author(s): 岡本貴行、鈴木宏治
  • Journal Title: Thrombosis Medicine Volume: 1巻 Pages: 17-176
• [Journal Article] 血液凝固制御因子プロテインSの構造と機能 (2011)
  • Author(s): 鈴木宏治、林辰弥
  • Journal Title: 臨床検査 Volume: 55巻 Pages: 340-346
• [Journal Article] Protein S-Tokushima(K155E) (2011)
  • Author(s): 鈴木宏治、林辰弥
  • Journal Title: 臨床検査 Volume: 55巻 Pages: 373-377
• [Journal Article] 血液凝固機序-血栓形成と細胞機能に及ぼす凝固因子の作用機序- (2011)
  • Author(s): 鈴木宏治
  • Journal Title: 脈管学 Volume: 51巻 Pages: 287-292
  • NAID: 10029767414
• [Journal Article] Connexin32 protects against vascular inflammation by modulating inflammatory cytokine expression by endothelial cells (2011)
  • Author(s): Okamoto T., Suzuki K, et al
  • Journal Title: Exp Cell Res Volume: 317 Pages: 348-355
  • Peer Reviewed
• [Journal Article] Effect of a prostaglandin I(2) analog on the expression of thrombomodulin in liver and spleen endothelial cells after an extensive hepatectomy (2011)
  • Author(s): Usui M, Suzuki K, et al
  • Journal Title: Sure Today Volume: 41 Pages: 230-236
  • Peer Reviewed
• [Journal Article] 凝固線溶系-凝固系の最近の進歩- (2011)
  • Author(s): 鈴木宏治
  • Journal Title: Thrombosis Medicine Volume: 1 Pages: 13-20
• [Journal Article] トロンボモジュリンを介しか凝固炎症反応と敗血症性DIC (2011)
  • Author(s): 岡本貴行、鈴木宏治
  • Journal Title: Thrombosis Medicine Volume: 1 Pages: 17-176
• [Journal Article] Protein S-Tokushima (K155E) (2011)
  • Author(s): 林辰弥、鈴木宏治
  • Journal Title: 臨床検査 Volume: 55 Pages: 373-377
• [Journal Article] Connexin32 protects against vascular inflammation by modulating inflammatory cytokine expression by endothelial cells. (2011)
  • Author(s): Okamoto T, Suauki K, et al.
  • Journal Title: Exp.Cell Res. Volume: 317 Pages: 348-355
  • Peer Reviewed
• [Journal Article] Phosphoinositide 3-kinase induced activation and cytoskeletal translocation of protein kinase CK2 in protease activated receptor 1-stimulated platelets (2010)
  • Author(s): Kurata T, Suzuki K, et al
  • Journal Title: Thromb. Res Volume: 125巻 Pages: 184-191
  • Peer Reviewed
• [Journal Article] The cytoprotective effects of addition of activated protein C into preservation solution on small-for-size grafts in rats (2010)
  • Author(s): Kuriyama N, Isaji S, Hamada T, Kishiwada M, Usui M, Sakurai H, Hayashi T, Suzuki K
  • Journal Title: Liver Transpl Volume: 16巻 Pages: 1-11
  • Peer Reviewed
• [Journal Article] トロンビン受容体 (2010)
  • Author(s): 岡本貴行、鈴木宏治
  • Journal Title: International Review of Thrombosis Volume: 5巻 Pages: 200-203
• [Journal Article] Activated protein C stimulates osteoblast proliferation via endothelial protein C receptor. (2010)
  • Author(s): Kurata T, Suauki K, et al.
  • Journal Title: Thromb.Res. Volume: 125 Pages: 184-191
  • Peer Reviewed
• [Journal Article] Phosphoinositide 3-kinase induced activation and cytoskeletal translocation of protein kinase CK2 in protease activated receptor 1-stimulated platelets. (2010)
  • Author(s): Nakanishi K, Suauki K, et al.
  • Journal Title: Thromb.Res. Volume: 126 Pages: 511-516
  • Peer Reviewed
• [Journal Article] An in vitro method for screening anti-platelet agents using a microchannel array flow analyzer. (2010)
  • Author(s): Kamada H, Suzuki K, et al.
  • Journal Title: Biorheology Volume: 47 Pages: 153-161
  • Peer Reviewed
• [Journal Article] Inhibition of allergic bronchial asthma by thrombomodulin is mediated by dendritic cells. (2010)
  • Author(s): Takagi T, Suzuki K, et al.
  • Journal Title: Am.J.Respir Crit.Care Med.(Epub ahead of print)
  • Peer Reviewed
• [Journal Article] LPS-Toll-like receptor-mediated signaling on expression of protein S and C4b-binding protein in the liver. (2010)
  • Author(s): Hayashi T, Suzuki K, et al.
  • Journal Title: Gastroenterol Res.Pract.(Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor activator (HGFA) : Its regulation by protein C inhibitor. (2010)
  • Author(s): Suauki K.
  • Journal Title: FEBS J. Volume: 277 Pages: 2223-2229
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor activator (HGFA) : Its regulation by protein C inhibitor (2010)
  • Author(s): Suzuki K
  • Journal Title: FEBS J. (In press)
  • Peer Reviewed
• [Journal Article] The cytoprotective effects of addition of activated protein C into preservation solution on small-for-size grafts in rats (2010)
  • Author(s): Kuriyama N, Isaji S, Hamada T, Kishiwada M, Ohsawa I, Usui M, Sakurai H, Tabata M, Hayashi T, Suzuki K
  • Journal Title: Liver Transpl. 16 Pages: 1-11
  • Peer Reviewed
• [Journal Article] Connexin32 is expressed in vascular endothelial cells and participates in gap junctional intercellular communication (2009)
  • Author(s): Okamoto T, Hayashi T, Suzuki K
  • Journal Title: Biochem Biophys Res Commun Volume: 382巻 Pages: 264-268
  • Peer Reviewed
• [Journal Article] Activated protein C prevents hepatic ischemia reperfusion injury in rats (2009)
  • Author(s): Kuriyama N, Isaji S, Suzuki K, Uemoto S, et al
  • Journal Title: Liver Int Volume: 29巻 Pages: 299-307
  • Peer Reviewed
• [Journal Article] Presence of thrombin-activatable fibrinolysis inhibitor in Helicobacter pylori-associated gastroduodenal disease (2009)
  • Author(s): Ikeda A, Yano Y, Sumida Y, Suzuki K, Taguchi O, Takei Y, et al
  • Journal Title: Helicobacter Volume: 14 Pages: 147-155
  • Peer Reviewed
• [Journal Article] Role of LOX-1 in monocyte adhesion-triggered redox, Akt/eNOS and Ca^<2+> signaling pathways in endothelial cells (2009)
  • Author(s): Sakamoto N, Suzuki K, Teramoto T, Maruyama Y, Takeishi Y, et al
  • Journal Title: J Cell Physiol Volume: 220 Pages: 706-715
  • Peer Reviewed
• [Journal Article] Cut-off values of D-dimer and soluble fibrin for prediction of deep vein thrombosis after orthopaedic surgery (2009)
  • Author(s): Sudo A, Wada H, Nobori T, Suzuki K, Uchida A, et al
  • Journal Title: Int J Hematol Volume: 89 Pages: 572-576
  • NAID: 10025161673
  • Peer Reviewed
• [Journal Article] Cut-off values of D-dimer and soluble fibrin for prediction of deep vein thrombosis after orthopaedic surgery (2009)
  • Author(s): Sudo A, Wada H, Nobori T, Yamada N, Ito M, Niimi R, Hasegawa M, Suzuki K, Uchida A.
  • Journal Title: Int J Hematol. 89 Pages: 572-576
  • NAID: 10025161673
  • Peer Reviewed
• [Journal Article] Role of LOX-1 in monocyte adhesion-triggered redox, Akt/eNOS and Ca^<2+> signaling pathways in endothelial cells (2009)
  • Author(s): Sakamoto N, Ishibashi T, Sugimoto K, Sawamura T, Sakamoto T, Inoue N, Saitoh SI, Kamioka M, Uekita H, Ohkawara H, Suzuki K, Teramoto T, Maruyama Y, Takeishi Y.
  • Journal Title: J Cell Physiol. 220 Pages: 706-715
  • Peer Reviewed
• [Journal Article] Connexin32 is expressed in vascular endothelial cells and participates in gap junctional intercellular communication (2009)
  • Author(s): Okamoto T, Akiyama M, Takeda M, Gabazza EC, Hayashi T, Suzuki K.
  • Journal Title: Biochem Biophys Res Commun. 382 Pages: 264-268
  • Peer Reviewed
• [Journal Article] Activated protein C prevents hepatic ischaemia reperfusion injury in rats (2009)
  • Author(s): Kuriyama N, Isaji S, Hamada T, Kishiwada M, Ohsawa I, Usui M, Sakurai H, Tabata M, Suzuki K, Uemoto S.
  • Journal Title: Liver Int 29 Pages: 299-307
  • Peer Reviewed
• [Presentation] Effect of protein C inhibitor on lipopolysaccharide-induced vascular permeability (2011)
  • Author(s): Yoshikawa T, Suzuki K, et al
  • Organizer: XXIII Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: Kyoto
  • Year and Date: 2011-07-28
• [Presentation] Anticoagulant activated protein C suppresses osteoclast differentiation via endothelial protein C receptor (2011)
  • Author(s): Yoshida K, Suzuki K, et al
  • Organizer: XXIII Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: Kyoto
  • Year and Date: 2011-07-28
• [Presentation] Gap junction protein, connexin32 regulates expression of tissue factor and inflammatory cytokines in the endothelial cells (2011)
  • Author(s): Okamoto T, Suzuki K, et al
  • Organizer: XXIII Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: Kyoto
  • Year and Date: 2011-07-26
• [Presentation] Effect of endotoxin and inflammatory cytokines on protein S and C4b-binding protein expressions in the liver cells (2011)
  • Author(s): Hayashi T, Suzuki K, et al
  • Organizer: XXIII Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: Kyoto
  • Year and Date: 2011-07-26
• [Presentation] The inhibition of lung metastasis by inactivation of coagulation activity may leadto dissemination of tumor cells (2011)
  • Author(s): Asanuma K, Suzuki K, et al
  • Organizer: XXIII Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: Kyoto
  • Year and Date: 2011-07-26
• [Presentation] The inhibition of lung metastasis by inactivation of coagulation activity may lead to dissemination of tumor cells (2011)
  • Author(s): Asanuma K, Suzuki K, et al
  • Organizer: XXIII Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: Kyoto
  • Year and Date: 2011-07-26
• [Presentation] Changes of behavior in C4b-binding protein and protein S in the inflammatory disease (2011)
  • Author(s): Ikejiri M, Suzuki K, et al
  • Organizer: XXIII Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: Kyoto
  • Year and Date: 2011-07-25
• [Presentation] Host PCI inhibits tumor growth, but promotes tumor metastasis by its procoagulant nature (2011)
  • Author(s): Akita N, Suzuki K, et al
  • Organizer: XXIII Congress of the International Society on Thrombosis and Haemostasis
  • Place of Presentation: Kyoto
  • Year and Date: 2011-07-21
• [Presentation] Connexin32, a gap junction protein, modulates inflammatory cytokine expression in vascular endothelial cells. (2010)
  • Author(s): Okamoto T, Suzuki K, et al.
  • Organizer: The 6th Asia Pacific Society on Thrombosis and Hemostasis Congress
  • Place of Presentation: インドネシア
  • Year and Date: 2010-10-15
• [Presentation] ギャップ結合を介した血管内皮細胞間相互作用は炎症と凝固の増幅を制御している (2010)
  • Author(s): 岡本貴行、鈴木宏治, 他
  • Organizer: 第33回日本血栓止血学会学術集会
  • Place of Presentation: 鹿児島市
  • Year and Date: 2010-04-23
• [Presentation] コネキシン32が血管内皮細胞の炎症性サイトカイン発現に及ぼす影響 (2010)
  • Author(s): 岡本貴行、鈴木宏治, 他
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸市
• [Book] スタンダード検査血液学第2版 (2012)
  • Author(s): 鈴木宏治, 他
  • Total Pages: 334
  • Publisher: 医歯薬出版
• [Book] 血管生物医学事典 (2011)
  • Author(s): 鈴木宏治, 他
  • Total Pages: 489
  • Publisher: 朝倉書店
• [Book] 予防ハンドブック-エキスパートオピニオン- (2010)
  • Author(s): 鈴木宏治, 他
  • Publisher: 南江堂
• [Book] 腫瘍薬学 (2010)
  • Author(s): 鈴木宏治, 他
  • Publisher: 南山堂
• [Book] 腫瘍薬学(川西正祐、中瀬一則、大井一弥編) (2010)
  • Author(s): 鈴木宏治
  • Total Pages: 573
  • Publisher: 南山堂
• [Book] 静脈血栓塞栓症予防ガイドブック(冨士武史、左近賢人編) (2010)
  • Author(s): 鈴木宏治
  • Total Pages: 241
  • Publisher: 南江堂
• [Book] 医学大事典 (2009)
  • Author(s): 鈴木宏治, 他
  • Total Pages: 702
  • Publisher: 医学書院
• [Book] 新臨床内科学第9版 (2009)
  • Author(s): 鈴木宏治, 他
  • Publisher: 医学書院
• [Book] スタンダード検査血液学第2版(日本検査血液学会編)
  • Author(s): 鈴木宏治, 他(共著)
  • Total Pages: 334
  • Publisher: 医歯薬出版、東京
• [Book] 血管生物医学事典(日本血管生物医学会編)
  • Author(s): 鈴木宏治, 他(共著)
  • Total Pages: 489
  • Publisher: 朝倉書店、東京