Impacts of Protein Quality Control in Cardiac Remodeling after Myocardial Infarction

• Project/Area Number: 24591092
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Kanazawa University
• Principal Investigator: USUI Soichiro 金沢大学, 大学病院, 助教 (50507043)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 慢性心不全 / 心臓リモデリング / 心筋梗塞 / 心破裂 / ユビキチンプロテオソーム / 虚血性心疾患 / タンパク分解 / 心不全 / マトリックスメタロプロテアーゼ / ユビキチンプロテアソーム

Outline of Final Research Achievements

Left ventricular (LV) remodeling following myocardial infarction (MI) has an important role on global cardiac function. Muscle atrophy F-box (MAFbx), an E3 ubiquitin ligase, induces skeletal muscle atrophy and cardiac remodeling under the condition of pressure overload, but the roles of MAFbx in MI is not well understood. Our aim is to determine if MAFbx contribute to cardiac remodeling following MI. MAFbx-knockout (KO) and wild-type (WT) mice were subjected to permanent coronary ligation to create MI. The infarct sizes 3 days after MI were not significantly different in WT and MAFbx KO mice. In comparison with WT mice, MAFbx KO mice were protected against early mortality due to cardiac rupture. MMP9 activity in risk areas 3 days after MI was significantly reduced in KO mice than in WT mice.
MAFbx protein level increase in acute phase after MI. Gene deletion of MAFbx deletion reduces mortality after MI and cardiac rupture, decreasing the activity of MMP9.

Research Products

• [Journal Article] MuRF1 negatively regulates pathological cardiac hypertrophy through downregulation of calcineurin A (2014)
  • Author(s): M.Yokota（他8名、7番目） et al
  • Journal Title: Circ Heart Fail Volume: 7 Issue: 3 Pages: 479-490
  • DOI: 10.1161/circheartfailure.113.000713
  • Peer Reviewed / Open Access
• [Journal Article] Rho-kinase activation in leukocytes plays a pivotal role in myocardial ischemia/reperfusion injury (2014)
  • Author(s): Kitano K, Usui S, Ootsuji H, Takashima S, Kobayashi D, Murai H, Furusho H, Nomura A, Kaneko S, Takamura M.
  • Journal Title: PLoS One. Volume: 9 Issue: 3 Pages: e92242-e92242
  • DOI: 10.1371/journal.pone.0092242
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hemodynamic collapse induced by general anesthesia in a patient with an unruptured thoracic aortic aneurysm: a case report (2013)
  • Author(s): Inoue, O, Murai, H, Kaneko, S, Usui, S, Furusho, H, Takamura, M
  • Journal Title: BMC CARDIOVASCULAR DISORDERS Volume: 13 Issue: 1 Pages: 122-122
  • DOI: 10.1186/1471-2261-13-122
  • Peer Reviewed
• [Journal Article] Adipose tissue derived stromal stem cell therapy in murine ConA-derived hepatitis is dependent on myeloid-lineage and CD4+ T-cell suppression. (2013)
  • Author(s): Higashimoto M, Sakai Y, Takamura M, Usui S, Nasti A, Yoshida K, Seki A, Komura T, Honda M, Wada T, Furuichi K, Ochiya T, Kaneko S.
  • Journal Title: Eur J Immunol Volume: 43 Issue: 11 Pages: 2956-68
  • DOI: 10.1002/eji.201343531
  • Peer Reviewed
• [Journal Article] Adipose tissue-derived stem cells as a regenerative therapy for a mouse steatohepatitis-induced cirrhosis model (2013)
  • Author(s): A Seki, S Y akai, T Komura, A Nasti, K Yoshida, M Higashimoto, M Honda, S Usui, M Takamura, T Takamura, T Ochiya, K Furuichi, T Wada, S Kaneko
  • Journal Title: Hepatology Volume: 58(3) Issue: 3 Pages: 1133-42
  • DOI: 10.1002/hep.26470
  • Peer Reviewed
• [Journal Article] Autophagy plays an essential role in mediating regression of hypertrophy during unloading of the heart. (2013)
  • Author(s): Hariharan N, Ikeda Y, Hong C, Alcendor RR, Usui S, Gao S, Maejima Y, Sadoshima J.
  • Journal Title: PLoS One. Volume: 8 Issue: 1 Pages: 51632-51632
  • DOI: 10.1371/journal.pone.0051632
  • Peer Reviewed
• [Presentation] MAFbx regulates cardiac rupture in mice with myocardial infarction (2015)
  • Author(s): Chikada, A; Usui, S; Kaneko, S; Sadoshima, J; Takamura, M
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪）
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] Muscle atrophy F-box (MAFbx) regulates neointimal formation during vascular remodeling in mice (2014)
  • Author(s): Kashimoto, M; Usui, S; Kusayama, T; Kitano, T; Kaneko, S; Sadoshima, J; Takamura, M
  • Organizer: ESC2014
  • Place of Presentation: Fira de Barcelona （スペイン バルセロナ）
  • Year and Date: 2014-08-31 – 2014-09-02
• [Presentation] Sphingosine 1-Phosphate Receptor 1 Signaling in Cardiac Fibroblaste Regulates Cardiac Hypertrophy and Fibrosis Through Angiotensin II and Interleukin-6
  • Author(s): Usui, S, Okura, S, Takashima, S, Takamura M, Kaneko S, Takuwa Y
  • Organizer: AHA2013
  • Place of Presentation: ジェイワールドコンベンションセンター （米国 ダラス）