2003 Fiscal Year Final Research Report Summary
Nuclear targeting of Akt enhances kinase activity and survival of cardiomyocytes
| Project/Area Number |
14570760
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
SHIRAISHI Isao Kyoto Prefectural University of Medicine, Assistant Professor, 医学研究科, 講師 (80295659)
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| Co-Investigator(Kenkyū-buntansha) |
HAMAOKA Kenji Kyoto Prefectural University of Medicine, Professor, 医学研究科, 教授 (60189602)
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| Project Period (FY) |
2002 – 2003
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| Keywords | Heart Failure / Gene Therapy / Apoptosis / Akt / Nuclear Localization signal |
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| Research Abstract |
Heart failure is associated with death of cardiomyocytes leading to loss of contractility. Previous studies using membrane-targeted Akt (myristolated-Akt), an enzyme involved in anti-apoptotic signaling, showed inhibition of cell death and prevention of pathogenesis induced by cardiomyopathic stimuli. However, recent studies by our group have found accumulation of activated Akt in the nucleus, suggesting that biologically relevant target(s) of Akt activity may be located there. To test this hypothesis, a targeted Akt construct was created to determine the anti-apoptotic action of nuclear Akt accumulation. Nuclear localization of the adenovirally-encoded Akt construct was confirmed by confocal microscopy. Cardiomyocytes expressing nuclear targeted Akt showed no evidence of morphologic remodeling such as altered myofibril density or hypertrophy. Nuclear targeted Akt significantly elevated levels of phospho-Akt and kinase activity and inhibited apoptosis as effectively as myristolated-Akt using in hypoxia-induced cell death. Transgenic overexpression of nuclear targeted Akt did not result in hypertrophic remodeling, altered cardiomyocyte DNA content or nucleation, or enhanced phosphorylation of typical cytoplasmic Akt substrates, yet transgenic hearts were protected from ischemia-reperfusion injury. Gene array analyses demonstrated changes in the transcriptional profile of Akt/nuc hearts compared to nontransgenic controls distinct from prior characterizations of Akt expression in transgenic hearts. Collectively, these experiments show that targeting of Akt to the nucleus mediates inhibition of apoptosis without hypertrophic remodeling, opening new possibilities for therapeutic applications of nuclear targeted Akt to inhibit cell death associated with heart disease.
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Research Products
(15 results)
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[Publications] Shiraishi I, Melendez J, Ahn Y, Wang GW, Vobdriska TM, Welch A, Schaefer E, Watsh K, Rosenzwicg A, Kajstura J, Ler A, Anversu P, Susaman SA: "Nuclear targeting of Akt enhances kinase activity and survival of cardiomyocyte."Circulation Research. 94(in press). (2004)
Description
「研究成果報告書概要(和文)」より
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[Publications] Torella D.Rota M, Nurzynska D, Musso E, Shiraishi I, Zias E, Walsh K, Rosenzweig A, Sussman M, Urbanek K, Nadal-Ginard B, Kajstura J, Anversa P, Leri A: "Stem cell and myocytes aging, heart falure and IGF-I overexpression."Circulation Research. 94. 514-524 (2004)
Description
「研究成果報告書概要(和文)」より
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[Publications] Shiraishi I, Yamamoto Y, Ozawa S, Kawakita A, Toiyama K, Tanaka T, Sakata K, Hayano T, Itoi T, Yamagishi M, Hamaoka K: "Appilcation of helical CT angiography with differential color imaging 31) reconstruction in the liagnosis of complicated congenital heart disease."Journal of Thoraci c and Cardiovascular Research. 125. 36-39 (2003)
Description
「研究成果報告書概要(和文)」より
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[Publications] Shiraishi I, Melendez J, Ahn Y, Wang GW, Vobdriska TM, Welch A, Schaefer E, Walsh K, Rosenzwieg A, Kajstura J, Leri A, Anversa P, Sussman MA.: "Nuclear targeting of Akt kinase activity and survival of cardiomyocyte."Cir Res.. 94(in press). (2004)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Torella D, Rota M, Nuzynska D, Musso E, Shiraishi I, Zias E, Walsh K, Rosenzweig A, Sussman M, Urbanek K, Nadal-Ginard B, Kajstura J, Anversa P, Leri A.: "Stem cell and myocyte aging, heart failure and IGF-1 overexpression."Circ Res.. 94. 514-524 (2004)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Shiraishi I, Yamamoto Y, Ozawa S, Kawakita A, Toiyama K, Tanaka T, Sakata K, Hayano T, Itoi T, Yamagishi M, Hamaoka K.: "Application of helical CT angiography with differential color imaging 3D reconstruction in the diagnosis of complicated congenital heart disease."J Thorac Cardiovasc Surg. 125. 36-39 (2003)
Description
「研究成果報告書概要(欧文)」より
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