| Project/Area Number |
21590926
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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 |
Circulatory organs internal medicine
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| Research Institution | Hamamatsu University School of Medicine |
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Principal Investigator |
SAOTOME Masao 浜松医科大学, 医学部・附属病院, 助教 (70509512)
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| Co-Investigator(Kenkyū-buntansha) |
KATOH Hideki 浜松医科大学, 医学部, 助教 (80314029)
SATOH Hiroshi 浜松医科大学, 医学部附属病院, 講師 (30293632)
HAYASHI Hideharu 浜松医科大学, 医学部, 教授 (50135258)
URUSHIDA Tsuyoshi 浜松医科大学, 医学部, 助教 (20334980)
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| Co-Investigator(Renkei-kenkyūsha) |
FUNAKI Makoto 徳島大学, 医学部・附属病院, 特任教授 (10467821)
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| Project Period (FY) |
2009 – 2011
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| Project Status |
Completed (Fiscal Year 2011)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2011: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2010: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2009: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 循環器 / 高血圧 / 糖尿病 / 循環器・高血圧 |
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| Research Abstract |
In failing hearts, cardiac myocytes mainly depend on fatty acids as an energy substrate because of myocardial insulin resistance, and result in further myocardial energy deficiencies and myocardial dysfunction, namely metabolic vicious cycle. Thus, recent investigations have focused on new agents to modulate the myocardial metabolic deficiency in heart failure.
We in this study have established a novel ex vivo cardiac insulin-resistant model, focused on substrate transporters(GLUT4 and FAT/CD36), and assessed the effects of several metabolic modulators on myocardial insulin resistance. The ex vivo insulin-resistant myocytes(insulin-resistant myocytes) were produced by inducing rat H9c2 myoblasts to differentiated myocytes and culturing myocytes with saturated fatty acids(palmitate, 0. 2 mM), which mimics the increased serum fatty acid levels during heart failure. The insulin-resistant myocytes exhibited an attenuated 2-deoxy-D-glucose uptake and suppressed insulin-signaling. Also, in the insulin-resistant myocytes, GLUT4(a glucose transporter) was inhibited the insulin-mediated translocation to plasma membrane, whereas FAT/CD36(a fatty acid transporter) was relocated in plasma membrane.
Our investigations concerning metabolic modulators revealed that the pretreatment myocytes with a CPT-1 inhibitor(perhexiline), which is an inhibitor of mitochondrial fatty acid uptake, partially restored palmitate-induced insulin-resistance. Furthermore, perhexiline protected myocytes from palmitate-induced mitochondrial dysfunction. From these results, the mitochondrial protection may be a key factor for the prevention against myocardial insulin resistance.
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