2019 Fiscal Year Final Research Report
The role of protein kinase N in cardiomyocyte
| Project/Area Number |
17K09571
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Cardiovascular medicine
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| Research Institution | Nagoya University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
天野 睦紀 名古屋大学, 医学系研究科, 准教授 (90304170)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Keywords | 心不全 |
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| Outline of Final Research Achievements |
Heart failure is a complex syndrome that results from structural or functional impairment of ventricular filling or blood ejection. Protein phosphorylation is a major and essential intracellular mechanism that mediates various cellular processes in cardiomyocytes in response to extracellular and intracellular signals. We demonstrated that RHOA activates 2 members of the PKN family of proteins, PKN1 and PKN2, in cardiomyocytes of mice with cardiac dysfunction. Cardiomyocyte-specific deletion of the genes encoding Pkn1 and Pkn2 protected mice from pressure overload induced cardiac dysfunction. Furthermore, we identified MRTFA as a novel substrate of PKN1 and PKN2 and found that MRTFA phosphorylation by PKN was considerably more effective than that by ROCK in vitro. Our results indicate that PKN1 and PKN2 activation causes cardiac dysfunction and is involved in the transition to heart failure, thus providing unique targets for therapeutic intervention for heart failure.
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| Free Research Field |
循環器内科
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、心筋特異的PKN1, PKN2欠損マウスが圧負荷やアンギオテンシンⅡに促進された心臓機能障害に抵抗性を示すことを証明した。PKNが、MRTFAのリン酸化によりMRTFAとG-アクチンの結合を阻害し、SRFを介した心肥大・線維化関連遺伝子を活性化することが機序と考えられた。PKNはMRTFAのリン酸化によりアクチン結合を介在し、心臓肥大・線維化を制御していることが証明され、心不全の新たな病態の解明、治療標的になることが示唆された。
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