| Project/Area Number |
19K16498
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 48020:Physiology-related
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
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| Keywords | Pulmonary Hypertension / Right Ventricle / Myocardium / Myofilament / X-ray Diffraction / Pressure-Volume Loop / Heart Failure / Sarcomere / Sympathetic Nervous Sys. / SSRIs / Cardiomyocyte |
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| Outline of Research at the Start |
Patients with pulmonary arterial hypertension (PAH) frequently develop right ventricle (RV) failure. The reasons why patients develop RV failure is unknown. In this project we will investigate how changes the heart muscle cells contribute to the development of RV failure in PAH. Firstly, we will examine if increased activity of the nervous system to the heart and changes in heart muscle energy utilization affects heart muscle cell function in a rat model of PAH. We will also investigate if using treatments that are targeted towards these changes are effective treatments to prevent RV failure.
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| Outline of Final Research Achievements |
In the right ventricle (RV) of rats with pulmonary arterial hypertension (PAH), it was found that progressive worsening of RV dysfunction occurred across the time course of PAH. Importantly, we revealed that changes at level of the actin-myosin cross-bridge and myofilament post-translational modifications were an underlying factor of global RV dysfunction in PAH.
Using a prevention model approach, PAH rats were chronically treated with hexarelin to attenuate sympathetic nervous system overdrive. Hexarelin treatment of PAH rats had no affect on RV remodelling or global RV function in PAH rats. Moreover, no effects of hexarelin were observed at the level of the cardiomyocyte or actin-myosin cross-bridge.
Lastly, intervention treatment with the GRK-2 inhibitor, paroxetine, in PAH rats was able to significantly improve RV systolic function and pulmonary hemodynamics compared to the vehicle-treated rats.
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| Academic Significance and Societal Importance of the Research Achievements |
In this project, we were able to reveal that the changes at the level of the myofilaments are closely linked with changes in global right ventricle (RV) function in the context of pulmonary arterial hypertension. GRK2-inhibition improved RV function in PAH, and will be further investigated.
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