anti-atherosclerotic and anti-cancer effects of AMPK activation

• Project/Area Number: 26461108
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Osaka University
• Principal Investigator: Tsukamoto Osamu 大阪大学, 医学系研究科, 助教 (80589151)
• Co-Investigator(Kenkyū-buntansha): 朝野 仁裕 大阪大学, 医学系研究科, 講師 (60527670)
• Co-Investigator(Renkei-kenkyūsha): SHINTANI Yasunori 大阪大学, 大学院医学系研究科, 助教 (20712243) ; HIGO Shuichiro (KATO Hisakazu) 大阪大学, 大学院医学系研究科, 助教 (00604034)
• Research Collaborator: Yan Yi 大阪大学, 大学院医学系研究科, 大学院生
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: AMPK / PDLIM5 / cell migration / ＡＭＰＫ / ｃｅｌｌ ｍｉｇｒａｔｉｏｎ / AMPキナーゼ / Pdlim5 / 細胞遊走

Outline of Final Research Achievements

We identified Pdlim5 as a novel AMPK substrate. AMPK phosphorylates Pdlim5 at Ser177. To investigate the role of Ser177 phosphorylation by AMPK, we produced the knockdown-and-rescue (KDR) system of vSMCs, in which endogenous Pdlim5 were replaced by exogenous EGFP-tagged-Pdlim5s. KDR/S177D-Pdlim5 cells exhibited perturbed cell migration compared with KDR/wild-type- and KDR/S177A-Pdlim5 cells even in the absence of AMPK activator. Furthermore, KDR/S177D-Pdlim5 cells exhibited defective lamellipodia formation. Consistent with this, KDR/S177D-Pdlim5 cells exhibited dislocation of Arp2/3 complex from the leading edge to cytosol and suppressed Rac1 activity. Finally, KDR/S177D-Pdlim5 cells disrupted the physical association with Arhgeg6, a guanine nucleotide exchange factor for Rac1. In conclusion, enhanced AMPK activation inhibits cell migration by interfering lamellipodia formation by suppressing the Arhgef6-Rac1-Arp2/3 signaling pathway via phosphorylating Pdlim5.

Research Products

• [Journal Article] A Development of Nucleic Chromatin Measurements as a New Prognostic Marker for Severe Chronic Heart Failure. (2016)
  • Author(s): Kanzaki M, Asano Y, Ishibashi-Ueda H, Oiki E, Nishida T, Asanuma H, Kato H, Oka T, Ohtani T, Tsukamoto O, Higo S, Kioka H, Matsuoka K, Sawa Y, Komuro I, Kitakaze M, Takashima S, Sakata Y.
  • Journal Title: PLoS One. Volume: 11 Issue: 2 Pages: e0148209-e0148209
  • DOI: 10.1371/journal.pone.0148209
  • Peer Reviewed / Open Access
• [Journal Article] Btg2 is a Negative Regulator of Cardiomyocyte Hypertrophy through a Decrease in Cytosolic RNA. (2016)
  • Author(s): Masumura Y, Higo S, Asano Y, Kato H, Yan Y, Ishino S, Tsukamoto O, Kioka H, Hayashi T, Shintani Y, Yamazaki S, Minamino T, Kitakaze M, Komuro I, Takashima S, Sakata Y.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 28592-28592
  • DOI: 10.1038/srep28592
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Identification of the Mtus1 Splice Variant as a Novel Inhibitory Factor Against Cardiac Hypertrophy. (2016)
  • Author(s): Ito S, Asakura M, Liao Y, Min KD, Takahashi A, Shindo K, Yamazaki S, Tsukamoto O, Asanuma H, Mogi M, Horiuchi M, Asano Y, Sanada S, Minamino T, Takashima S, Mochizuki N, Kitakaze M.
  • Journal Title: J Am Heart Assoc. Volume: 5 Issue: 7
  • DOI: 10.1161/jaha.116.003521
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Augmented AMPK activity inhibits cell migration by phosphorylating the novel substrate Pdlim5. (2015)
  • Author(s): Yan Y, Tsukamoto O, Nakano A, Kato H, Kioka H, Ito N, Higo S, Yamazaki S, Shintani Y, Matsuoka K, Liao Y, Asanuma H, Asakura M, Takafuji K, Minamino T, Asano Y, Kitakaze M, Takashima S.
  • Journal Title: Nat Commun. Volume: 6 Issue: 1 Pages: 6137-6137
  • DOI: 10.1038/ncomms7137
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Higdla is a oositive regulaator of cytochrome c oxidase (2015)
  • Author(s): T. Hayashi, Y. Asano, Y. Shintani, H. Aoyama, H. Kioka, O. Tsukamoto, M. Hikita, K. Shinzawa-Itoh, K. Takajuji, S. Higo, H. Kato, S. Yamazaki, K. Matsuoka, A. Nakano, H. Asanuma, M. Asakura, T. Minamino, Y. Goto, T. Ogura, M. Kitakaze, I. Komuro, Y. Sakata, T. Tsukihara, S. Yoshikawa, S. Takashima
  • Journal Title: Proc. Nat. Acad. Sci. U.S.A. Volume: 112 Issue: 5 Pages: 1553-1558
  • DOI: 10.1073/pnas.1419767112
  • Peer Reviewed / Open Access
• [Journal Article] Different Implications of Functional Tricuspid Regurgitation Between Heart Failure (HF) With Reduced Ejection Fraction (EF) and HF With Preserved EF (2015)
  • Author(s): Tsukamoto O, Kitakaze M
  • Journal Title: Circulation Journal Volume: 79 Issue: 7 Pages: 1448-1449
  • DOI: 10.1253/circj.CJ-15-0560
  • NAID: 130005083967
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Recent Progress and Next Challenges in the Treatment of Symptomatic Heart Failure in Japan (2015)
  • Author(s): Tsukamoto O, Kitakaze M
  • Journal Title: Circulation Journal Volume: 79 Issue: 11 Pages: 2322-2323
  • DOI: 10.1253/circj.CJ-15-1014
  • NAID: 130005104913
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Targeting lysosomal Ca2+ to reduce reperfusion injury. (2015)
  • Author(s): Tsukamoto O, Asanuma H, Kitakaze M.
  • Journal Title: Cardiovasc Res Volume: 108 Issue: 3 Pages: 321-323
  • DOI: 10.1093/cvr/cvv242
  • Peer Reviewed
• [Journal Article] PDE5 inhibitor efficacy is estrogen dependent in female heart disease. (2014)
  • Author(s): 32.Sasaki H, Nagayama T, Blanton RM, Seo K, Zhang M, Zhu G, Lee DI, Bedja D, Hsu S, Tsukamoto O, Takashima S, Kitakaze M, Mendelsohn ME, Karas RH, Kass DA, Takimoto E.
  • Journal Title: J Clin Invest. Volume: 124 Issue: 6 Pages: 2464-2464
  • DOI: 10.1172/jci70731
  • Peer Reviewed / Open Access
• [Journal Article] Noninvasive and quantitative live imaging reveals a potential stress-responsive enhancer in the failing heart. (2014)
  • Author(s): Matsuoka K, Asano Y, Higo S, Tsukamoto O, Yan Y, Yamazaki S, Matsuzaki T, Kioka H, Kato H, Uno Y, Asakura M, Asanuma H, Minamino T, Aburatani H, Kitakaze M, Komuro I, Takashima S.
  • Journal Title: FASEB J. Volume: 28(4) Issue: 4 Pages: 1870-9
  • DOI: 10.1096/fj.13-245522
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Evaluation of intra-mitochondrial ATP levels identifies G0/G1 switch gene 2 as a positive regulator of oxidative phosphorylation (2013)
  • Author(s): Kioka H, Kato H, Fujikawa M, Tsukamoto O, Suzuki T, Imamura H, Nakano A, Higo S, Yamazaki S, Matsuzaki T, Tkafuji K, Asanuma H, Asakura M, Minamino T, Shintani Y, Yoshida M, Noji H, Kitakaze M, Komuro I, Asano Y and Takashima S
  • Journal Title: PNAS Volume: 111 Issue: 1 Pages: 273-278
  • DOI: 10.1073/pnas.1318547111
  • Peer Reviewed / Open Access
• [Remarks] 細胞遊走を制御する蛋白質を同定
  • URL: http://medbio.sakura.ne.jp/cms/wp-content/uploads/2015/02/6ba705b56624d11b034d9b434b1bc0e8.pdf