Basic research and clinical trial regarding vessel regeneration and cardiac protection with a derivative of erythropoietin

• Project/Area Number: 18590806
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Niigata University
• Principal Investigator: KATO Kiminori Niigata University, Medial & Dental Hospital, Instructor (00303165)
• Co-Investigator(Kenkyū-buntansha): HANAWA Haruo Niigata University, Graduate School of Medical and Dental Sciences, Lecturer (40282983) ; NAKAZAWA Mikio Niigata University, Graduate School of Medical and Dental Sciences, Professor (80143759) ; IBBA Ken Niigata University, Medical & Dental Hospital, Lecturer (60313540) ; AIZAWA Yoshifusa Niigata University, Graduate School of Medical and Dental Sciences, Professor (50143780)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,830,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥330,000); Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2006: ¥2,400,000 (Direct Cost: ¥2,400,000)
• Keywords: erythropoietin / myocardial infarction / asialoerythropoietin / 急性心筋梗塞 / アシアロエリスロポエチン / エリスロポエチン誘導体

Research Abstract

I. Basic research regarding the mechanism of vessel regeneration through use of a derivative of erythropoietin
(1) The mechanism of asialoerythropoietin: The effects of limb ischemia with asialoerythropoietin are as strong as cell therapy with bone marrow implantation. Asialoerythropoietin induces an anti-apoptotic effect via the production of Bcl-xL as well as angiogenesis via production of PLGF in skeletal muscle. (2) The effect of erythropoietin and asialoerythropoietin in a reperfusion injury model of rat myocardial ischemia: We applied continuous intravenous infusion of 500 IU/kg/day of erythropoietin or asialoerythropoietin using an osmotic pump immediately after making this ischemic model for 28 days. A decrease of the scar area in the heart was found in both groups, but the effect of asialoerythropoietin was superior to that of erythropoietin. In the former group, an increase of VEGF, CD31, eNOS, and Bcl-xL of myocyte was determined, and it was supposed that asialoerythropoietin has strong anti-apoptotic and angiogenic effects.
II. Clinical trial of erythropoietin therapy for acute myocardial infarction.
(1) Eight cases in Niigata University, 20 in Showa University, one in Dokkyo University, and 4 cases in the Kobari Hospital were registered in this study. (2) Acute effect of erythropoietin (within one month): We administered an intravenous drip infusion of erythropoietin for 30 minutes within 24hours after admission to the hospital in the treatment group. There were no cases indicating adverse events such as hypertension or polycythemia. (3) Chronic effect of erythropoietin: We plan to get all clinical data of each patient including cardiac function 6 months after injection, and will investigate the final results after completion of the protocol in August this year. (4) Serum hepcidin concentration: Hepcidin plays a central role in iron metabolism. We found an interesting change in the pattern of the hepcidin concentration after acute myocardial infarction and are preparing to submit this result.

Research Products

• [Journal Article] Alteration of IL-17 Related Protein Expressions in Experimental Autoimmune Myocarditis and Inhibition of IL-17 by IL-10-Ig Fusion Gene Transfer (2008)
  • Author(s): Chang, H, Hanawa, H, Yoshida, T, Hayashi, M, Liu, H, Ding, L, Otaki, K, Hao, K, Yoshida, K, Kato, K, Toba, K, Kodama, M, Maruyama, H, Miyazaki, J, Aizawa, Y
  • Journal Title: Circ J 72(5) Pages: 813-819
  • NAID: 110006680563
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Serum erythropoietin level as a marker of limb ischemia (2007)
  • Author(s): Ozawa, T. Kato, K., 他16名
  • Journal Title: Int J Cardiol (in press)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Prognostic factors of critical limb ischemia after autologous bone marrow implantation (2007)
  • Author(s): Oda, M. Kato, K., 他15名
  • Journal Title: J Cardiol 50 Pages: 235-42
  • NAID: 10019775044
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Serum erythropoietin level as a marker of limb ischemia (2007)
  • Author(s): Ozawa, T, Kato, K, Toba, K, Oda, M, Isoda, M, Asami, F, Ikarashi, N, Yanagawa, T, Moriyama, M, Higashimura, M, Kitajima, T, Otaki, K, Takayama, T, Hirono, S, Okura, Y, Hanawa, H, Kodama, M, Aizawa, Y
  • Journal Title: Int J Cardiol
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Characterization of outpatients with systolic dysfunction in a Japanese community by total enumeration (2007)
  • Author(s): Okura, Y, Ohno, Y, Suzuki, K, Taneda, K, Ramadan, MM, Mitsuma, W, Tanaka, K, Kashimura, T, Ito, M, Ishizuka, O, Kato, K, Hanawa, H, Honda, Y, Kodama, M, Aizawa, Y
  • Journal Title: Circ J 71(7) Pages: 1004-1012
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Characterization of outpatients with isolated diastolic dysfunction and evaluation of the burden in a Japanese community: Sado Heart Failure Study (2007)
  • Author(s): Okura, Y, Ohno, Y, Ramadan, MM, Suzuki, K, Taneda, K, Obata, H, Tanaka, K, Kashimura, T, Ishizuka, O, Kato, K, Hanawa, H, Honda, Y, Kodama, M, Aizawa, Y
  • Journal Title: Circ J 71(7) Pages: 1013-1021
  • NAID: 110006318398
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prognostic factors for critical limb ischemia after autologous bone marrow implantation (2007)
  • Author(s): Oda, M, Kato, K, Toba, K, Otaki, K, Kitajima, T, Ikarashi, N, Yanagawa, T, Higashimura, M, Asami, F, Isoda, M, Ozawa, T, Moriyama, M, Hirono, S, Okura, Y, Hanawa, H, Kodama, M, Aizawa, Y
  • Journal Title: J Cardiol 50(4) Pages: 235-242
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Serum erythropoietin level as a marker of limb ischemia (2007)
  • Author(s): Ozawa, T. Kato, K. 他16名
  • Journal Title: Int J Cardiol (in press)
  • Peer Reviewed
• [Journal Article] Prognostic factors of critical limb ischemia after autologous bone marrow implantation (2007)
  • Author(s): Oda, M. Kato, K. 他15名
  • Journal Title: J Cardiol 50 Pages: 235-42
  • NAID: 10019775044
  • Peer Reviewed
• [Journal Article] エリスロポエチンを用いた循環器疾患治療(総説) (2007)
  • Author(s): 加藤公則、他2名
  • Journal Title: 呼吸と循環 55 Pages: 991-996
• [Journal Article] Erythroid cells play essential roles in angiogenesis by bone marrow cell implantation (2006)
  • Author(s): Ozawa T, Toba K, Kato K, et. al.
  • Journal Title: J Mol Cell Cardiol 40 Pages: 629-38
  • NAID: 120006735349
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Erythroid cells play essential roles in angiogenesis by bone marrow cell implantation (2006)
  • Author(s): Ozawa, T, Toba, K, Kato, K, Minagawa, S, Saigawa, T, Hanawa, H, Makiyama, Y, Moriyama, M, Honma, K, Isoda, M, Hasegawa, G, Naito, M, Takahashi, M, Aizawa, Y
  • Journal Title: J Mol Cell Cardiol 40(5) Pages: 629-638
  • NAID: 120006735349
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Marked decrease of plasma VEGF after implantation of autologous bone marrow mononuclear cells in a patient with critical limb ischemia-a case report (2006)
  • Author(s): Ozawa, T, Kato, K, Sanada, H, Makiyama, Y, Saigawa, T, Souda, S, Hashimoto, S, Furukawa, T, Toba, K, Kodama, M, Fujiwara, H, Namura, O, Hayashi, J, Yoshimura, N, Aizawa, Y
  • Journal Title: Angiology 57(2) Pages: 235-239
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The optimal cut-off point of C-reactive protein as an optional component of metabolic syndrome in Japan (2006)
  • Author(s): Oda, E, Oohara, K, Abe, A, Veeraveedu, PT, Watanabe, K, Kato, K, Aizawa, Y
  • Journal Title: Circ J 70(4) Pages: 384-388
  • NAID: 110004497222
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Gender differences in correlations among cardiovascular risk factors (2006)
  • Author(s): Oda, E, Abe, M, Kato, K, Watanabe, K, Veeraveedu, PT, Aizawa, Y
  • Journal Title: Gend Med 3(3) Pages: 196-205
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cardioprotective effects of recombinant human erythropoietin in rats with experimental autoimmune myocarditis (2006)
  • Author(s): Mitsuma, W, Ito, M, Kodama, M, Fuse, K, Okamura, K, Minagawa, S, Kato, K, Hanawa, H, Toba, K, Nakazawa, M, Aizawa, Y
  • Journal Title: Biochem Biophys Res Commun 344(3) Pages: 987-994
  • NAID: 120006735347
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mechanism that underlie the angiogenesis by bone marrow implantation, and an application of erythropoietin for angiogenic therapy (2006)
  • Author(s): Kato, K, Toba, K, Oda, M, Ikarashi, N, Minagawa, S, Isoda, M, Aizawa, Y
  • Journal Title: J Jpn Coll Angiol 46 Pages: 595-601
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hydrodynamic-based delivery of an interleukin-22-Ig fusion gene ameliorates experimental autoimmune myocarditis in rats (2006)
  • Author(s): Chang, H, Hanawa, H, Liu, H, Yoshida, T, Hayashi, M, Watanabe, R, Abe, S, Toba, K, Yoshida, K, Elnaggar, R, Minagawa, S, Okura, Y, Kato, K, Kodama, M, Maruyama, H, Miyazaki, J, Aizawa, Y
  • Journal Title: J Immunol 177(6) Pages: 3635-3643
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 末梢動脈疾患に対する細胞治療における工夫、末梢単核球移植追加治療とエリスロポエチン併用治療について (2006)
  • Author(s): 加藤公則, 鳥羽 健, 相澤義房
  • Journal Title: 日本アフェレシス学会雑誌 25・3 Pages: 210-6
• [Journal Article] Erythroid cells play essential roles in angiogenesis by bone marrow cell implantation (2006)
  • Author(s): Ozawa T, Toba K, Kato K, et al.
  • Journal Title: J Mol Cell Cardiol 40・5 Pages: 629-38
  • NAID: 120006735349
• [Journal Article] Marked decrease of plasma VEGF after implantation of autologous bone marrow mononuclear cells in a patient with critical limb ischemia (2006)
  • Author(s): Ozawa T, Kato K, Toba K, et al.
  • Journal Title: Angiology 57・2 Pages: 235-9
• [Journal Article] Cardiorotective effects of recombinant human erythropoietin in rats with experimental autoimmune myocarditis (2006)
  • Author(s): Mitsma W, Kato K, Toba K, et
  • Journal Title: Biochem Biophys Res Commun 344・3 Pages: 987-94
• [Journal Article] Mechanism that underlie the angiogenesis by bone marrow implantation, and an application of erythropoietin for angiogenic therapy (2006)
  • Author(s): Kato K, Toba K, Aizawa Y, et al.
  • Journal Title: J Jpn Coll Angiol 46・5 Pages: 595-601
• [Journal Article] Hydrodynamic-based delivery of an interleukin-22-Ig fusion gene ameliorates experimental autoimmune myocarditis in rats (2006)
  • Author(s): Chang H, Hanawa H, Kato K, et al.
  • Journal Title: J Immunol 177・6 Pages: 3635-43
• [Presentation] Ex Vivo Expanded Erythroblast-Transplantation(Autologous)Therapy, EVEETA, a Novel Remedy for Severe Limb Ischemia (2008)
  • Author(s): Masato, Oda, Kiminori, Kato, Ken, Toba, Tsugumi, Takayama, Keita, Otaki, Takao, Yanagawa, Noboru, Ikarashi, Takuya, Ozawa, Satoru, Hirono, Haruo, Hanawa, Yoshifusa, Aizawa
  • Organizer: The 72nd Annual Scientific Meeting of the Japanese Circulation Society
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Intravenous erythropoietin administration attenuated monocrotaline-induced rat pulmonary hypertension (2008)
  • Author(s): Noboru, Ikarashi, Kiminori, Kato, Ken, Toba, Tsugumi, Takayama, Masato, Oda, Keita, Otaki, Takao, Yanagawa, Fuyuki, Asami, Takuya, Ozawa, Satoru, Hirono, Haruo, Hanawa, Makoto, Kodama, Yoshifusa, Aizawa
  • Organizer: The 72nd Annual Scientific Meeting of the Japanese Circulation Society
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Expression of hepcidin increases in cardiomyocytes under myocarditis and myocardial infarction (2008)
  • Author(s): Haruo, Hanawa, Manabu, Isoda, Ritsuo, Watanabe, Tsuyoshi, Yoshida, Keita, Otaki, Kiminori, Kato, Yuji, Okura, Makoto, Kodama, Yoshifusa, Aizawa
  • Organizer: The 72nd Annual Scientific Meeting of the Japanese Circulation Society
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Asialoerythropoietin is a Hopeful Drug for Angiogenesis Therapy (2007)
  • Author(s): 五十嵐 登、加藤公則、他
  • Organizer: 第71回日本循環器学会学術集会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2007-03-17
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Asialoerythropoietin is a hopeful drug for angiogenesis therapy (2007)
  • Author(s): Noboru, Ikarashi, Kiminori, Kato, Ken, Toba, Keita, Otaki, Masato, Oda, Takao, Yanagawa, Manabu, Isoda, Shiro, Minagawa, Takuya, Ozawa, Takashi, Saigawa, Haruo, Hanawa, Makoto, Kodama, Yoshifusa, Aizawa
  • Organizer: The 71st Annual Scientific Meeting of the Japanese Circulation Society
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Asialoerythropoietin showed cardioprotective effects on ischemia-reperfusion injury model in mouse (2006)
  • Author(s): Fuyuki, Asami, Manabu, Isoda, Kiminori, Kato, Masato, Oda, Keita, Otaki, Noboru, Ikarashi, Takao, Yanagawa, Takuya, Ozawa, Satoru, Hirono, Haruo, Hanawa, Yoshifusa, Aizawa
  • Organizer: The 72nd Annual Scientific Meeting of the Japanese Circulation Society
  • Description: 「研究成果報告書概要(欧文)」より
• [Remarks] 「研究成果報告書概要(和文)」より
  • URL: http://www.med.niigata-u.ac.jp/in1/godoproject/saisei.html
• [Remarks]
  • URL: http://www.med.niigata-u.ac.jp/in1/godoproject/saisei.html