Regeneration of the heart by proliferation of cardiac myocytes : Research for clinical implication

• Project/Area Number: 15390243
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Akita University
• Principal Investigator: ITO Hiroshi Akita University, School of Medicine, Professor, 医学部, 教授 (10232464)
• Project Period (FY): 2003 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥14,100,000 (Direct Cost: ¥14,100,000); Fiscal Year 2005: ¥4,700,000 (Direct Cost: ¥4,700,000); Fiscal Year 2004: ¥4,500,000 (Direct Cost: ¥4,500,000); Fiscal Year 2003: ¥4,900,000 (Direct Cost: ¥4,900,000)
• Keywords: cardiac myocytes / cell cycle / cyclin D1 / NLS / regeneration therapy / cyclin D1 / アデノウィルスベクター

Research Abstract

Myocyte loss caused by cardiovascular diseases leads to irreversible deficits in cardiac function, because of the inability of the remaining myocytes to reconstitute the damaged myocardium. To elucidate the inhibitory mechanism of cardiomyocyte proliferation would have therapeutic importance for myocardium regeneration. We show that cyclin D1, a key regulator for the G1-to-S phase transition, is induced by mitogenic stimulation but localizes predominantly cytoplasmic in neonatal cardiomyocytes. Nevertheless, cytoplasmic cyclin D1 assembled with cyclin-dependent kinase 4 (CDK4), and p21^<Cip1>, which provides nuclear localization signals (NLSs) for the cyclin D1/CDK4 complex. Coexpression of CDK4 with a cyclin D1 mutant directly linked to viral NLSs, but not wild-type cyclin D1, induced cell cycle progression leading to cell division. Moreover, cyclin D1/CDK4 nuclear import promoted cell cycle reentry of cardiomyocytes in the adult rat heart. Further we performed in vivo study using rats with heart failure by introducing the adenovirus vector in the heart. Cyclin D1 nuclear import is critical for inducing proliferation of cardiomyocytes that otherwise have quit limited proliferative capacity, and this can be applied to a novel therapeutic strategy for heart failure.

Research Products

• [Journal Article] HMG-CoA Reductase Inhibitor Fluvastatin Prevents Angiotensin II-Induced Cardiac Hypertrophy via Rho Kinase and Inhibition of Cyclin D1. (2006)
  • Author(s): Morikawa K, Adachi S, Maejima Y, Adachi M, Suzuki J, Kitajima S, Ito H, Isobe M.
  • Journal Title: Life Sciences (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] HMG-CoA Reductase Inhibitor Fluvastatin Prevents Angiotensin II-Induced Cardiac Hypertrophy via Rho Kinase and Inhibition of Cyclin D1. (2006)
  • Author(s): Morikawa K, Adachi S, Maejima Y, Adachi M, Suzuki J, Kitajima S, Ito H, M Isobe
  • Journal Title: Life Sciences (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Nitric Oxide Inhibits myocardial apoptosis by preventing caspase-3 activity via S-nitrosylation. (2005)
  • Author(s): Maejima Y, Adachi A, Morikawa K, Ito H, Isobe M.
  • Journal Title: J Mol Cell Cardiol 38 Pages: 163-174
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genomic organization and functional analysis of murine PKD2L1. (2005)
  • Author(s): Murakami, M., Ohba, T., Xu, F.et al.
  • Journal Title: J. Biol. Chem 280 Pages: 5626-5635
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Nitric Oxide Inhibits myocardial apoptosis by preventing caspase-3 activity via S-nitrosylation. (2005)
  • Author(s): Maejima Y, Adachi A, Morikawa K, Ito H, Isobe M.
  • Journal Title: J Mol Cell Cardiol. 38 Pages: 163-174
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genomic organization and functional analysis of murine PKD2L1. (2005)
  • Author(s): Murakami, M., Ohba, T., Xu, F., Shida, S., Satoh, E., Ono, K., Miyoshi, I., Watanabe, H., Ito.H., Iijima, T.
  • Journal Title: J.Biol.Chem. 280 Pages: 5626-5635
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genomic organization and functional analysis of murine PKD2L1. (2005)
  • Author(s): Murakami, M., Ohba, T., Xu, F., Shida, S., Satoh, E., Ono, K., Miyoshi, I., Watanabe, H., Ito, H., Iijima, T.
  • Journal Title: J.Biol.Chem. 280 Pages: 5626-5635
• [Journal Article] Genomic organization and functional analysis of murine PKD2L1. (2005)
  • Author(s): Murakami, M., Ohba, T., Xu, F., Shida, S., Satoh, E., Ono, K., Miyoshi, I., Watanabe, H., Ito, H., Iijima, T.
  • Journal Title: J.Biol.Chem. (In press)
• [Journal Article] Initial clinical cases using an NF-kB decoy at the site of the coronary stenting for prevention of restenosis. (2004)
  • Author(s): Suzuki J, Ito H, Gotoh R, Morishita R, Egashira K, Isobe M.
  • Journal Title: Circ J 68 Pages: 270-271
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Initial clinical cases using an NF-kB decoy at the site of the coronary stenting for prevention of restenosis. (2004)
  • Author(s): Suzuki J, Ito H, Gotoh R, Morishita R, Egashira K, Isobe M.
  • Journal Title: Circ J. 68 Pages: 270-271
• [Journal Article] Nitric Oxide Inhibits Ischemia/Reperfusion-Induced MyocardialApoptosis by Modulating Cyclin A-Associated Kinase Activity. (2003)
  • Author(s): Maejima Y, Adachi A, Ito H, Nobori K, Tamamori-Adachi M, Isobe M.
  • Journal Title: Cardiovasc Res 59 Pages: 308-320
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Critical role of Cyclin D1 nuclear import in cardiomyocyte proliferation. (2003)
  • Author(s): Tamamori-Adachi M, Ito H, S Piyamas, et al.
  • Journal Title: Circ Res 92 Pages: 12-19
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Nitric Oxide Inhibits Ischemia/Reperfusion-Induced Myocardial Apoptosis by Modulating Cyclin A-Associated Kinase Activity (2003)
  • Author(s): Maejima Y, Adachi A, Ito H, Nobori K, Tamamori-Adachi M, Isobe M.
  • Journal Title: Cardiovasc Res. 59 Pages: 308-320
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Critical role of Cyclin D1 nuclear import in cardiomyocyte proliferation. (2003)
  • Author(s): Tamamori-Adachi M, Ito H, S Piyamas, Adachi S, Hiroe M, Shimizu M, Kawauchi J, Sunamori M, Marumo F, Kitajima S, Ikeda M.
  • Journal Title: Circ Res. 92 Pages: 12-19
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Nitric Oxide Inhibits Ischemia/Reperfusion-Induced Myocardial Apoptosis by Modulating Cyclin A-Associated Kinase Activity. (2003)
  • Author(s): Maejima Y, Adachi A, Ito H, Nobori K, Tamamori-Adachi M, Isobe M.
  • Journal Title: Cardiovasc Res. 59 Pages: 308-320
• [Journal Article] Attenuation of Experimental Autoimmune Myocarditis by Blocking Activated T Cells through Inducible Costimulatory Molecule Pathway. (2003)
  • Author(s): Futamatsu H, Suzuki J, Kosuge H, Yokoseki O, Kamada M, Ito H, Inobe M, Isobe
  • Journal Title: Cardiovasc Res. 59 Pages: 95-104
• [Journal Article] Specific acceptance of cardiac allografts by a combined treatment with inducible costimulator-immunoglobulin (ICOSIg) and CTLA4Ig. (2003)
  • Author(s): Kosuge H, Suzuki J, Gotoh R, Koga N, Ito H, Isobe M, Inobe M, Uede T.
  • Journal Title: Transplant 75 Pages: 1374-1379