Elucidation of the regulatory mechanism of natriuretic hormone expression for oral heart failure drug development

• Project/Area Number: 15H04820
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Osaka University
• Principal Investigator: TAKASHIMA Seiji 大阪大学, 生命機能研究科, 教授 (90379272)
• Co-Investigator(Kenkyū-buntansha): 朝野 仁裕 大阪大学, 医学系研究科, 講師 (60527670) ; 塚本 蔵 大阪大学, 医学系研究科, 助教 (80589151)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2017: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2016: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2015: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
• Keywords: 心不全 / ナトリウム利尿ホルモン / エンハンサー / シグナル伝達 / 創薬 / BNP / 転写因子 / メカニカルストレス / 循環器・高血圧 / 発現制御

Outline of Final Research Achievements

We clarified how natriuretic peptides ANP and BNP, which are elevated and become severity markers during heart failure and are also used as therapeutic agents, are regulated in vivo. The results of this project are as follows.(1) Expression of heart failure in ANP and BNP is regulated by about 600 bp enhancer positioned about 20 kb upstream of the gene, and is induced by binding of factors.(2) Even in catecholamine stimulation, this expression signal is not transmitted when the movement of the heart is stopped, and this signal is transmitted by the two types of mechanostress, so that mechanical stimulation is involved in this signal induction even at the cellular level.
It is clarified how signal transduction in heart failure is transmitted, and it is expected to lead to the development of drugs for the treatment of heart failure targeting these signals.

Research Products

• [Journal Article] Genetic basis of cardiomyopathy and the genotypes involved in prognosis and left ventricular reverse remodeling (2018)
  • Author(s): Tobita T, Nomura S, Fujita T, Morita H, Asano Y, Onoue K, Ito M, Imai Y, Suzuki A, Ko T, Satoh M, Fujita K, Naito AT, Furutani Y, Toko H, Harada M, Amiya E, Hatano M, Takimoto E, Shiga T, Nakanishi T, Sakata Y, Ono M, Saito Y, Takashima S, Hagiwara N, Aburatani H, Komuro I.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 20114-20119
  • DOI: 10.1038/s41598-018-20114-9
  • Peer Reviewed / Open Access
• [Journal Article] Heat Failure Phenotypes Induced by Knockdown of DAPIT in Zebrafish: A New Insight into Mechanism of Dilated Cardiomyopathy. (2017)
  • Author(s): Nagata Y, Yamagishi M, Konno T, Nakanishi C, Asano Y, Ito S, Nakajima Y, Seguchi O, Fujino N, Kawashiri MA, Takashima S, Kitakaze M, Hayashi K.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 17417-17417
  • DOI: 10.1038/s41598-017-17572-y
  • Peer Reviewed / Open Access
• [Journal Article] Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells. (2017)
  • Author(s): Ikeda K, Kinoshita M, Kayama H, Nagamori S, Kongpracha P, Umemoto E, Okumura R, Kurakawa T, Murakami M, Mikami N, Shintani Y, Ueno S, Andou A, Ito M, Tsumura H, Yasutomo K, Ozono K, Takashima S, Sakaguchi S, Kanai Y, Takeda K.
  • Journal Title: Cell Reports Volume: 21 Issue: 7 Pages: 1824-1838
  • DOI: 10.1016/j.celrep.2017.10.082
  • Peer Reviewed / Open Access
• [Journal Article] Novel Synthesized Radical-Containing Nanoparticles Limit Infarct Size Following Ischemia and Reperfusion in Canine Hearts. (2017)
  • Author(s): Asanuma H, Sanada S, Yoshitomi T, Sasaki H, Takahama H, Ihara M, Takahama H, Shinozaki Y, Mori H, Asakura M, Nakano A, Sugimachi M, Asano Y, Minamino T, Takashima S, Nagasaki Y, Kitakaze M.
  • Journal Title: Cardiovasc Drugs Ther. Volume: 31 Issue: 5-6 Pages: 501-510
  • DOI: 10.1007/s10557-017-6758-6
  • Peer Reviewed / Open Access
• [Journal Article] Targeted Genome Replacement via Homology-directed Repair in Non-dividing Cardiomyocytes (2017)
  • Author(s): Ishizu T, Higo S, Masumura Y, Kohama Y, Shiba M, Higo T, Shibamoto M, Nakagawa A, Morimoto S, Takashima S, Hikoso S, Sakata Y.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 9363-9363
  • DOI: 10.1038/s41598-017-09716-x
  • Peer Reviewed / Open Access
• [Journal Article] Alternative exon skipping biases substrate preference of the deubiquitylase USP15 for mysterin/RNF213, the moyamoya disease susceptibility factor (2017)
  • Author(s): Kotani Y, Morito D, Sakata K, Ainuki S, Sugihara M, Hatta T, Iemura SI, Takashima S, Natsume T, Nagata K
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 44293-44293
  • DOI: 10.1038/srep44293
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Targeted Therapy for Acute Autoimmune Myocarditis with Nano-Sized Liposomal FK506 in Rats. (2017)
  • Author(s): Okuda K, Fu HY, Matsuzaki T, Araki R, Tsuchida S, Thanikachalam PV, Fukuta T, Asai T, Yamato M, Sanada S, Asanuma H, Asano Y, Asakura M, Hanawa H, Hao H, Oku N, Takashima S, Kitakaze M, Sakata Y, Minamino T.
  • Journal Title: PLoS One. Volume: 11 Issue: 8 Pages: e0160944-e0160944
  • DOI: 10.1371/journal.pone.0160944
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Adenovirus vector-based incorporation of a photo-cross-linkable amino acid into proteins in human primary cells and cancerous cell lines. (2016)
  • Author(s): Kita A, Hino N, Higashi S, Hirota K, Narumi R, Adachi J, Takafuji K, Ishimoto K, Okada Y, Sakamoto K, Tomonaga T, Takashima S, Mizuguchi H, Doi T.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 36946-36946
  • DOI: 10.1038/srep36946
  • Peer Reviewed / Open Access
• [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] 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] 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] Neuromuscular regulation in zebrafish by a large AAA+ ATPase/ubiquitin ligase, mysterin/RNF213. (2015)
  • Author(s): Kotani Y, Morito D, Yamazaki S, Ogino K, Kawakami K, Takashima S, Hirata H, Nagata K.
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 16161-16161
  • DOI: 10.1038/srep16161
  • Peer Reviewed / Open Access
• [Journal Article] Beyond Homozygosity Mapping: Family-Control analysis based on Hamming distance for prioritizing variants in exome sequencing. (2015)
  • Author(s): Imai A, Nakaya A, Fahiminiya S, Tétreault M, Majewski J, Sakata Y, Takashima S, Lathrop M, Ott J.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 12028-12028
  • DOI: 10.1038/srep12028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Data Mining as a Powerful Tool for Creating Novel Drugs in Cardiovascular Medicine: The Importance of a "Back-and-Forth Loop" Between Clinical Data and Basic Research. (2015)
  • Author(s): Kitakaze M, Asakura M, Nakano A, Takashima S, Washio T.
  • Journal Title: Cardiovasc Drugs Ther. Volume: 29 Issue: 3 Pages: 309-15
  • DOI: 10.1007/s10557-015-6602-9
  • Peer Reviewed
• [Journal Article] Usefulness and Limitation of Protein Mass Analysis (2015)
  • Author(s): Takashima S
  • Journal Title: Circulation Journal Volume: 79 Issue: 12 Pages: 2549-2550
  • DOI: 10.1253/circj.CJ-15-1101
  • NAID: 130005110910
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed