Mechanism of diastolic dysfunction in pressure-overloaded mouse heart
| Project/Area Number |
15590773
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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 | The Jikei University School of Medicine |
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Principal Investigator |
HONGO Kenichi The Jikei University School of Medicine, Lecturer, 医学部, 講師 (00256447)
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| Co-Investigator(Kenkyū-buntansha) |
KAWAI Makoto The Jikei University School of Medicine, Lecturer, 医学部, 講師 (40277025)
KOMUKAI Kimiaki The Jikei University School of Medicine, Lecturer, 医学部, 講師 (60360145)
KUSAKARI Yoichiro The Jikei University School of Medicine, Lecturer, 医学部, 講師 (80338889)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2003: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Keywords | Mouse heart / Intracellular calcium concentration / Diastolic dysfunction / Acidosis / SERCA / 細胞内カルシウム濃度 / アンジオテンシンII / 心不全 |
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| Research Abstract |
We investigated the mechanism of diastolic dysfunction in heart failure. In hypertrophied heart following transverse aortic constriction (TAG), we found severe hypertrophy in vivo heart and in myocyte morphology. However, we could not estimate adequate physiological function from the failing heart following TAC. Therefore, we changed the model to acidosis condition and genetically engineered mouse to perform further study. During acidosis condition (extracellular pH was changed from 7.4 to 6.8), intracellular Ca transient (CaT) measured by aequorin method increased although isometric tension decreased dramatically. During recovery phase following acidosis, tension increased transiently which was followed by a gradual recovery to steady-state. Time course of CaT was significantly prolonged during acidosis indicating a cause of diastolic dysfunction. We then performed similar experiments under different muscle lengths. In shorter muscle length, transient tension increase and following st
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eady-state tension during recovery phase from acidosis were significantly preserved compared to longer muscle length. To clarify the mechanism of diastolic dysfunction further, we used genetically engineered mice in which the function of Ca pump in sarcoplasmic reticulum (SERCA) was modulated. In SERCA overexpressing heart (SERCA-TG), amplitudes of CaT and tension were increased and time courses of both signals were accelerated. Ca uptake rate measured using saponin skinned preparation was accelerated in SERCA-TG. In contrast, overexpression of inhibitory protein of SERCA (Sarcolipin-TG) diminished the amplitudes of CaT and tension and delayed the time courses of both signals. Ca uptake rate was also decreased in Sarcolipin-TG. We applied acidosis condition to SERCA-TG. Reduction of tension during acidosis and steady-state tension during recovery phase from acidosis were greatly preserved in SERCA-TG. Time course of CaT did not change significantly during acidosis. These results suggest that length-dependent modulation could be beneficial to contractile dysfunction during acidosis and SERCA function is a major contributor of diastolic dysfunction. Less
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Report
(4 results)
Research Products
(16 results)
