Target of Rapamycm, as a therapeutic target of heart failure

• Project/Area Number: 17390235
• 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: Kyoto University
• Principal Investigator: SHIOI Tetsuo Kyoto University, Departrnent of Cardiovascular Medicine, Assistant Professor (50360095)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥16,420,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥1,320,000); Fiscal Year 2007: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2006: ¥5,200,000 (Direct Cost: ¥5,200,000); Fiscal Year 2005: ¥5,500,000 (Direct Cost: ¥5,500,000)
• Keywords: Heart Failure / Aging / Insulin / Rapamycin / Hypertrophy / 糖尿病 / シロリムス

Research Abstract

Heart failure is an age-related disease. Since advanced age is a major risk factor for heart failure, aging process of heart may he a substrate for heart failure. Although age-associated morphological and functional changes of heart are well studied, little is known about the molecular mechanism of cardiac aging and how cardiac aging is involved in the development of heart failure. Recent genetic studies using short lived model organisms identify several molecules that play critical roles in life van determination. Among the molecular mechanisms identified, insulin signaling pathway is likely to be important The purpose of this study is to examine the role of insulin signaling pathway in cardiac aging and heat failure.
The results are as follows.
1. Rapamycin improved cardiac function of an animal model of dilated cardiomyopathy.
2. Resveratrol ameliorated myocardial injury of experimental autoimmune myocarditis.
3. Suppression of insulin signaling prevented cardiac aging in mice.
4. Modulation of glycolysis attenuated heart failure in a rat model of hypertension.
It is hoped that a novel treatment for heart failure in older people is developed by modulating insulin signaling pathway.

Research Products

• [Journal Article] MURC, a muscle-restricted coiled-coil protein that modulates the Rho/ROCK pathway, induces cardiac dysfunction and conduction disturbance. (2008)
  • Author(s): Ogata T, Ueyama T, Isodono K, Tagawa M, Takehara N, Kawashima T, Harada K, Takahashi T, Shioi T, Matsubara H, Oh H.
  • Journal Title: Mol Cell Biol. 28 Pages: 3424-36
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism. (2008)
  • Author(s): Ha T, Hua F, Liu X, Ma J, McMullen JR, Shioi T, Izumo S, Kelley J, Gao X, Browder W, Williams DL, Kao RL, Li C.
  • Journal Title: Cardiovasc Res. 78 Pages: 546-53
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] a muscle-restricted coiled-coil protein that modulates the Rho/ROCK pathway, induces cardiac dysfunction and conduction disturbance (2008)
  • Author(s): Ogata, T., Ueyama, T., Isodono, K., Tagawa, M., Takehara, N., Kawashima, T., Harada, K., Takahashi, T., Shioi, T., Matsubara, H., Oh, H., MURC
  • Journal Title: Mol Cell Biol 28 Pages: 3424-36
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism (2008)
  • Author(s): Ha, T., Hua, F., Liu, X., Ma, J., McMullen, JR., Shioi, T., Izumo, S., Kelley, J., Gao, X., Browder, W., Williams, DL., Kao, RL., Li, C
  • Journal Title: Cardiovasc Res 78 Pages: 546-53
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] MURC, a muscle-restricted coiled-coil protein that modulates the Rho/ROCK pathway, induces cardiac dysfunction and conduction disturbance. (2008)
  • Author(s): Ogata T, Ueyama T, Isodono K, Tagawa M, Takehara N, Kawashima T, Harada K, Takahashi T, Shioi T, Matsubara H, Oh H.
  • Journal Title: Mol Cell Biol.
  • Peer Reviewed
• [Journal Article] Lipopolysaccharide-induced myocardial protection againstischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism. (2008)
  • Author(s): Ha T, Hua F, Liu X, Ma J, McMullen JR, Shioi T, Izumo S, Kelley J, Gao X, Browder W, Williams DL, Kao RL, Li C.
  • Journal Title: Cardiovasc Res.
  • Peer Reviewed
• [Journal Article] A Conserved Role for Phosphatidylinositol 3-Kinase but Not Akt Signaling in Mitochondrial Adaptations that Accompany Physiological Cardiac Hypertrophy. (2007)
  • Author(s): O'neill BT, Kim J, Wende AR, Theobald HA, Tuinei J, Buchanan J, Guo A, Zaha VG, Davis DK, Schell JC, Boudina S, Wayment B, Litwin SE, Shioi T, Izumo S, Birnbaum MJ, Abel ED.
  • Journal Title: Cell Metab. 6 Pages: 294-306
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Resistin, an adipocytokine, offers protection against acute myocardial infarction. (2007)
  • Author(s): Gao J, Chang Chua C, Chen Z, Wang H, Xu X, C Hamdy R, McMullen JR, Shioi T, Izumo S, Chua BH.
  • Journal Title: J Mol Cell Cardiol. 43 Pages: 601-9
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Resveratrol ameliorates experimental autoimmune myocarditis. (2007)
  • Author(s): Yoshida Y, Shioi T, Izumi T.
  • Journal Title: Circ J. 71 Pages: 397-404
  • NAID: 110006224211
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Protective effects of exercise and phosphoinositide 3-kinase(p110alpha)signaling in dilated and hypertrophic cardiomyopathy. (2007)
  • Author(s): McMullen JR, Amirahmadi F, Woodcock EA, Schinke-Braun M, Bouwman RD, Hewitt KA, Mollica JP, Zhang L, Zhang Y, Shioi T, Buerger A, Izumo S, Jay PY, Jennings GL
  • Journal Title: Proc Natl Acad Sci. USA. 104 Pages: 612-7
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] A Conserved Role for Phosphatidylinositol 3-Kinase but Not Akt Signaling in Mitochondrial Adaptations that Accompany Physiological Cardiac Hypertrophy (2007)
  • Author(s): O'neill, BT., Kim, J., Wende, AR., Theobald, HA., Tuinei, J., Buchanan, J., Guo, A., Zaha, VG., Davis, DK., Schell, JC., Boudina, S., Wayment, B., Litwin, SE., Shioi, T., Izumo, S., Birnbaum, MJ., Abel, ED
  • Journal Title: Cell Metab 6 Pages: 294-306
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Resistin, an adipocytokine, offers protection against acute myocardial infarction (2007)
  • Author(s): Gao, J., Chang, Chua, C., Chen, Z., Wang, H., Xu, X., C., Hamdy, R., McMullen, JR, Shioi, T., Izumo, S., Chua, BH
  • Journal Title: JMol Cell Cordial 43 Pages: 601-9
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Resveratrol ameliorates experimental autoimmune myocarditis (2007)
  • Author(s): Yoshida, Y., Shioi, T., Izumi, T
  • Journal Title: Circ J 71 Pages: 397-404
  • NAID: 110006224211
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Protective effects of exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated and hypertrophic cardiomyopathy (2007)
  • Author(s): McMullen, JR., Amirahmadi, F., Woodcock, EA., Schinke-Braun, M., Bouwman, RD., Hewitt, KA., Mollica, JP., Zhang, L., Zhang, Y., Shioi, T., Buerger, A., Izumo, S., Jay, PY., Jennings, GL
  • Journal Title: Proc Natl Acad Sci. USA 104 Pages: 612-7
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Resistin, an adipocytokine, offers protection againstacute myocardial infarction. (2007)
  • Author(s): Gao J, Chang Chua C, Chen Z, Wang H, Xu X, C Hamdy R, McMullen JR, Shioi T, Izumo S, Chua BH
  • Journal Title: J Mol Cell Cardiol. 43 Pages: 601-609
  • Peer Reviewed
• [Journal Article] Resveratrol ameliorates experimental autoimmune myocarditis. (2007)
  • Author(s): Yoshida Y, Shioi T, Izumi T.
  • Journal Title: Circ J. 71・3 Pages: 397-404
  • NAID: 110006224211
• [Journal Article] Protective effects of exercise and phosphoinositide 3-kinase (p110alpha) signaling in dilated and hypertrophic cardiomyopathy. (2007)
  • Author(s): McMullen JR, Amirahmadi F, Woodcock EA, Schinke-Braun M, Bouwman RD, Hewitt KA, Mollica JP, Zhang L, Zhang Y, Shioi T, Buerger A, Izumo S, Jay PY, Jennings GL.
  • Journal Title: Proc Natl Acad Sci U S A. 104・2 Pages: 612-617
• [Journal Article] Central neurotranspeptide, alpha-melanocyte-stimulating horm one(alpha-MSH)is upregulated in patients with congestive heart failure. (2006)
  • Author(s): Yamaoka-Tojo M, Tojo T, Shioi T, Masuda T, Inomata T, Izumi T.
  • Journal Title: Intern Med. 45 Pages: 429-34
  • NAID: 130000076805
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Angiotensin II receptor antagonist attenuates expression of aging markers in diabetic mouse heart. (2006)
  • Author(s): Kosugi R, Shioi T, Watanabe-Maeda K, Yoshida Y, Takahashi K, Machida Y, Izumi T.
  • Journal Title: Circ J. 70 Pages: 482-8
  • NAID: 110004497239
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Central neurotranspeptide, alpha-melanocyte-stimulating hormone (alpha-MSH) is upregulated in patients with congestive heart failure (2006)
  • Author(s): Yamaoka-Tojo, M., Tojo, T., Shioi, T., Masuda, T., Inomata, T., Izumi, T
  • Journal Title: Intern Med 45 Pages: 429-34
  • NAID: 130000076805
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Angiotensin II receptor antagonist attenuates expression of aging markers in diabetic mouse heart (2006)
  • Author(s): Kosugi, R., Shioi, T., Watanabe-Maeda, K., Yoshida, Y., Takahashi, K., Machida, Y., Izumi, T
  • Journal Title: Circ J 70 Pages: 482-8
  • NAID: 110004497239
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Central neurotranspeptide, alpha-melanocyte-stimulating hormone (alpha-MSH) is upregulated in patients with congestive heart failure. (2006)
  • Author(s): Yamaoka-Tojo M, Tojo T, Shioi T, Masuda T, Inomata T, Izumi T.
  • Journal Title: Intern Med. 45・7 Pages: 429-434
  • NAID: 130000076805
• [Journal Article] Angiotensin II receptor antagonist attenuates expression of aging markers in diabetic mouse heart. (2006)
  • Author(s): Kosugi R, Shioi T, Watanabe-Maeda K, Yoshida Y, Takahashi K, Machida Y, Izumi T.
  • Journal Title: Circ J. 70・4 Pages: 482-488
  • NAID: 110004497239
• [Journal Article] Attenuation of cardiac hypertrophy by inhibiting both mTOR and NFkappaB activation in vivo. (2005)
  • Author(s): Ha T, Li Y, Gao X, McMullen J R, Shioi T, Izumo S, Kelley JL, Zhao A, Haddad GE, Williams DL, Browder IW, Kao RL, Li C.
  • Journal Title: Free Radic Biol Med. 39 Pages: 1570-80
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Attenuation of cardiac hypertrophy by inhibiting both mTOR and NFIcappaB activation in vivo (2005)
  • Author(s): Ha, T., Li, Y., Gao, X., McMullen, JR., Shioi, T., Izumo, S., Kelley, JL., Zhao, A., Haddad, GE., Williams, DL., Browder, IW., Kao, RL., Li, C
  • Journal Title: Free Radio Rio! Med 39 Pages: 1570-80
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Attenuation of cardiac hypertrophy by inhibiting both mTOR and NFkappaB activation in vivo. (2005)
  • Author(s): Ha T, Li Y, Gao X, McMullen JR, Shioi T, Izumo S, Kelley JL, Zhao A, Haddad GE, Williams DL, Browder IW, Kao RL, Li C.
  • Journal Title: Free Radic Biol Med. 39・12 Pages: 1570-1580
• [Presentation] Suppression of Insulin Signaling Attenuates Cardiac Aging in Mice. (2007)
  • Author(s): Inuzuka Y, Shioi T, Kato T, Tamaki Y, Kawashima K, Iwanaga Y, Kita T, Yoshida Y, Kosugi R, Watanabe-Maeda K, Machida Y, Izumi T.
  • Organizer: The 79th Scientific Sessions of American Heart Association
  • Place of Presentation: Orland, USA
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Metabolomic Analysis of the Transition from Cardiac Hypertrophy to Failure. (2007)
  • Author(s): Kato T, Shioi T, Niizuma S, Tamaki Y, Inuzuka Y, Kawashima T, Iwanaga Y, Kita T, Soga T.
  • Organizer: The 79th Scientific Sessions of American Heart Association
  • Place of Presentation: Orland, USA
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Suppression of Insulin Signaling Attenuates Cardiac Aging in Mice (2007)
  • Author(s): Inuzuka, Y., Shioi, T., Kato, T., Tamaki, Y., Kawashima, K., Iwanaga, Y., Kita, T., Yoshida, Y., Kosugi, R., Watanabe-Maeda, K., Machida, Y., Izumi, T
  • Organizer: The 79th Scientific Sessions of American Heart Association
  • Place of Presentation: Orland, USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Metabolomic Analysis of the Transition from Cardiac Hypertrophy to Failure (2007)
  • Author(s): Kato, T., Shioi, T., Niizuma, S., Tamaki, Y., Inuzuka, Y., Kawashima, T., Iwanaga, Y., Kita, T., Soga, T
  • Organizer: The 79th Scientific Sessions of American Heart Association
  • Place of Presentation: Orland, USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Suppression of Insulin Signaling Attenuates Cardiac Aging in Mice. (2007)
  • Author(s): Inuzuka Y, Shioi T, Kato T, Tamaki Y, Kawashima K, Iwanaga Y, Kita T, Yoshida Y, Kosugi R, Watanabe-Maeda K, Machida Y, Izumi T.
  • Organizer: The 79th Scientific Sessions of American Heart Association
  • Place of Presentation: Orland, USA.
• [Presentation] Metabolomic Analysis of the Transition from Cardiac Hypertrophy to Failure. (2007)
  • Author(s): Kato T, Shioi T, Niizuma S, Tamaki Y, Inuzuka Y, Kawashima T, Iwanaga Y, Kita T, Soga T.
  • Organizer: The 79th Scientific Sessions of American Heart Association
  • Place of Presentation: Orland, USA.
• [Presentation] Chronic Administration of Endogenous Inotropic Peptide, Apelin, Prevents Left Ventricular Remodeling and Improves Survival in Hypertensive Rats with Heart Failure. (2007)
  • Author(s): Tamaki Y, Iwanaga Y, Niizuma S, Kawashima T, Kato T, Inuzuka Y, Ono K, Shioi T, Kita T.
  • Organizer: The 79th Scientific Sessions of American Heart Association
  • Place of Presentation: Orland, USA.
• [Book] 新・心臓病プラクティス9 (2007)
  • Author(s): 塩井哲雄, 佐藤洋.
  • Total Pages: 2
  • Publisher: 文光堂
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 心不全を予防する (2007)
  • Author(s): 塩井哲雄, 犬塚康孝.
  • Total Pages: 18
  • Publisher: 中山書店
  • Description: 「研究成果報告書概要(和文)」より