The role of protein kinase N in cardiomyocyte

• Project/Area Number: 17K09571
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Nagoya University
• Principal Investigator: TAKEFUJI MIKITO 名古屋大学, 医学系研究科, 助教 (20709117)
• Co-Investigator(Kenkyū-buntansha): 天野 睦紀 名古屋大学, 医学系研究科, 准教授 (90304170)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 心不全 / キナーゼ

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.

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。

Research Products

• [Journal Article] Protein Kinase N Promotes Stress-Induced Cardiac Dysfunction Through Phosphorylation of Myocardin-Related Transcription Factor A and Disruption of Its Interaction With Actin. (2019)
  • Author(s): Sakaguchi T, Takefuji M, Wettschureck N, Hamaguchi T, Amano M, Kato K, Tsuda T, Eguchi S, Ishihama S, Mori Y, Yura Y, Yoshida T, Unno K, Okumura T, Ishii H, Shimizu Y, Bando YK, Ohashi K, Ouchi N, Enomoto A, Offermanns S, Kaibuchi K, Murohara T.
  • Journal Title: Circulation. Volume: 140 Issue: 21 Pages: 1737-1752
  • DOI: 10.1161/circulationaha.119.041019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cardiomyocytes capture stem cell-derived, anti-apoptotic microRNA-214 via clathrin-mediated endocytosis in acute myocardial infarction. (2019)
  • Author(s): Eguchi S, Takefuji M, Sakaguchi T, Ishihama S, Mori Y, Tsuda T, Takikawa T, Yoshida T, Ohashi K, Shimizu Y, Hayashida R, Kondo K, Bando YK, Ouchi N, Murohara T.
  • Journal Title: J Biol Chem. Volume: 294 Issue: 31 Pages: 11665-11674
  • DOI: 10.1074/jbc.ra119.007537
  • Peer Reviewed / Open Access
• [Journal Article] Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction. (2017)
  • Author(s): Tsuda T, Takefuji M, Wettschureck N, Kotani K, Morimoto R, Okumura T, Kaur H, Eguchi S, Sakaguchi T, Ishihama S, Kikuchi R, Unno K, Matsushita K, Ishikawa S, Offermanns S, Murohara T.
  • Journal Title: J Exp Med. Volume: 214 Issue: 7 Pages: 1877-1877
  • DOI: 10.1084/jem.20161924
  • Peer Reviewed / Open Access / Int'l Joint Research