Targeting insulin signaling pathway to develop a new therapy for heart failure.
| Project/Area Number |
15390252
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Kitasato University |
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Principal Investigator |
SHIOI Tetsuo Kitasato University, School of Medicine, Department of Internal Medicine and Cardiology, Research Associate, 医学部, 助手 (50360095)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | Heart failure / Diabetes / Insulin / Rapamycin / Sirolimus / 心肥大 / 増殖因子 |
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| Research Abstract |
To develop a new strategy that target insulin signaling, we examined a role of phosphoinositide 3-kinase (PI3K) or mammalian Target of Rapamycin (mTOR) in animal models of heart failure.
1.Effect of rapamycin on a rat model of autoimmune myocarditis.
We administered rapamycin, a selective inhibitor of mTOR, to rats immunized cardiac myosin. Rapamycin improved survival of the rats with autoimmune myocarditis. Rapamycin significantly reduced inflammation and fibrosis. Cardiac contractile function assessed by echocardiography was decreased in myosin immunized rats, and rapamycin preserved cardiac function. Rapamycin significantly attenuated autoimmune myocarditis of rats.
2.Role of PI3K and mTOR in thyroid hormone induced cardiac hypertrophy.
Hyperthyroidism causes cardiac hypertrophy and heart failure. We administered thyroid hormone to wild type mice or transgenic mice expressing dominant-negative PI3K specifically in cardiac muscle cells. Thyroid hormone increased heart weight by 27% in wi
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ld type mice. However, thyroid hormone increased heart weight of dominant-negative PI3K transgenic mice by 9%. We also administered rapamycin to thyroid hormone treated mice. Mice treated with thyroid hormone and rapamycin showed increase in heart weight by 9%. Thus, PI3K and mTOR are necessary for thyroid hormone induced cardiac hypertrophy in mice.
3.Identification of target genes of rapamycin in growing mice hearts.
We administered rapamycin or vehicle to one week old mice. The treatment was continued for a week and the mice were sacrificed. We compared the gene expression profiling using microarray analysis. Expressions of cyclin B3, eukaryotic translation initiation factor 3, stormal cell derived factor 2 like protein were decreased. Expressions of growth arrest specific gene 8, c-myc binding protein, autophagy 12-like protein were increased.
In conclusion, rapamycin significantly attenuated cardiac hypertrophy and heart failure induced by myocarditis and hyperthyroidism. Rapamycin may be a therapeutic modality for heart failure. Less
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Report
(3 results)
Research Products
(19 results)
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[Journal Article] The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase (p110alpha) pathway.2004
Author(s)
McMullen JR^*, Shioi T^*, Huang WY, Zhang L, Tarnavski O, Bisping E, Schinke M, Kong S, Sherwood MC, Brown J, Riggi L, Kang PM, Izumo S (^*equally contributed)
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Journal Title
J Biol Chem. 279
Pages: 4782-4793
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Deletion of ribosomal S6 kinases does not attenuate pathological, physiological, or insulin-like growth factor 1 receptor-phosphoinositide 3-kinase-induced cardiac hypertrophy.2004
Author(s)
McMullen JR, Shioi T, Zhang L, Tarnavski O, Sherwood MC, Dorfman AL, Longnus S, Pende M, Martin KA, Blenis J, Thomas G, Izumo S
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Journal Title
Mol Cell Biol. 24
Pages: 6231-6240
Description
「研究成果報告書概要(欧文)」より
Related Report
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