Novel heart failure pharmacotherapy that targets nuclear signaling pathway in cardiac myocytes

• Project/Area Number: 15K09108
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Department of Clinical Research, National Hospital Organization Kyoto Medical Center
• Principal Investigator: HASEGAWA Koji 独立行政法人国立病院機構(京都医療センター臨床研究センター), 展開医療研究部, 研究部長 (50283594)
• Research Collaborator: MORIMOTO Tatsuya 静岡県立大学 ; SUNAGAWA Yoichi 静岡県立大学 ; KATANASAKA Yasufumi 静岡県立大学 ; MIYAZAKI Yusuke 静岡県立大学
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 循環器・高血圧 / シグナル伝達 / 薬学 / トランスレーショナルリサーチ

Outline of Final Research Achievements

Heart failure is a leading cause of cardiovascular death. During development and deterioration of heart failure, cardiomyocytes undergo maladaptive hypertrophy, accompanied by re-induction of the fetal gene program. The transcriptional coactivator p300, an intrinsic histone acetyltransferase (HAT), is an important factor involved in the regulation of gene expression during cardiomyocyte hypertrophy. The natural compound, curcumin, possesses p300-specific HAT inhibitory activity. Our previous study demonstrated that curcumin prevents the development of cardiac hypertrophy by inhibiting p300-HAT activity. Here, we showed that demethoxycurcumin and bisdemethoxycurcumin, other major curcuminoids isolated from Curcuma longa, inhibited p300-HAT activity and cardiomyocyte hypertrophy to almost the same extent as curcumin. Thus, structural differences among the three compounds may not be involved in the inhibitory effects on p300-HAT activity and cardiac hypertrophy.

Research Products

• [Journal Article] MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol. (2016)
  • Author(s): Nishiga M, Horie T, Kuwabara Y, Nagao K, Baba O, Nakao T, Nishino T, Hakuno D, Nakashima Y, Nishi H, Nakazeki F, Ide Y, Koyama S, Kimura M, Hanada R, Nakamura T, Inada T, Hasegawa K, Conway SJ, Kita T, Kimura T, Ono K.
  • Journal Title: Circ Res. Volume: - Issue: 5 Pages: 835-847
  • DOI: 10.1161/circresaha.116.309528
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Highly absorptive curcumin reduces serum atherosclerotic low-density lipoprotein levels in patients with mild COPD (2016)
  • Author(s): Funamoto M, Sunagawa Y, Katanasaka Y, Miyazaki Y, Imaizumi A, Kakeya H, Yamakage H, Satoh-Asahara N, Komiyama M, Wada H, Hasegawa K, Morimoto T.
  • Journal Title: International Journal of Chronic Obstructive Pulmonary Disease Volume: 11 Pages: 2029-2034
  • Peer Reviewed / Open Access
• [Journal Article] Tyrosine phosphorylation of RACK1 triggers cardiomyocyte hypertrophy by regulating the interaction between p300 and GATA4. (2016)
  • Author(s): Suzuki H, Katanasaka Y, Sunagawa Y, Miyazaki Y, Funamoto M, Wada H, Hasegawa K, Morimoto T.
  • Journal Title: Biochim Biophys Acta. Volume: 1862 Pages: 1544-1557
  • Peer Reviewed / Open Access
• [Journal Article] Effect of Statins on Atherogenic Serum Amyloid A and α1-Antitrypsin Low-Density Lipoprotein Complexes (2016)
  • Author(s): Miyazaki Y, Katanasaka Y, Sunagawa Y, Sae Hirano-Sunagawa, Funamoto M, Eriko Morimoto, Komiyama M, Shimatsu A, Satoh-Asahara N, Yamakage H, Wada H, Hasegawa K, Morimoto T.
  • Journal Title: International Journal of Cardiology Volume: 3 Pages: 332-336
  • Peer Reviewed / Open Access
• [Journal Article] Functional Analysis of GATA4 Complex, a Cardiac Hypertrophy-response Transcriptional Factor, Using a Proteomics Approach. (2016)
  • Author(s): Sunagawa Y, Katanasaka Y, Wada H, Hasegawa K, Morimoto T
  • Journal Title: Yakugaku Zasshi Volume: 136(2) Pages: 151-6
  • NAID: 130005121459
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Analysis on Time Course Changes of Adipocytokine Levels and Abdominal Obesity after Quitting Smoking (2017)
  • Author(s): Maki Komiyama, Hiromichi Wada, Hajime Yamakage, Noriko Asahara, Sayaka Shimada, Akira Shimatsu, Tatsuya Morimoto, Yuko Takahashi, Koji Hasegawa
  • Organizer: American Heart Association EPI/LIFESTYLE 2017
  • Int'l Joint Research
• [Presentation] Quitting Smoking Reduces Lectin-like low- density lipoprotein receptor-1 index, an Independent Cardiovascular Risk Marker of Vascular Inflammation (2017)
  • Author(s): Maki Komiyama, Hiromichi Wada, Hajime Yamakage, Noriko Asahara, Sayaka Shimada, Masaharu Akao, Tatsuya Morimoto, Yuko Takahashi, Tatsuya Sawamura, Koji Hasegawa
  • Organizer: American Heart Association EPI/LIFESTYLE 2017
  • Int'l Joint Research
• [Presentation] Histone Acetylation Domain by p300 are Changed During the Transition From Cardiac Hypertrophy to Heart Failure Circulation. 2017;136:A18911. (Abstract 18911) (2017)
  • Author(s): Masafumi Funamoto, Yoichi Sunagawa, Yasufumi Katanasaka, Yusuke Miyazaki, Hiromichi Wada, Koji Hasegawa and Tatsuya Morimoto
  • Organizer: American Heart Association Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] Statins reduced atherogenic oxidatively modified low-density lipoprotein complexes: STAT-LVDF study (2016)
  • Author(s): Yusuke Miyazaki, Yasufumi Katanasaka, Yoichi Sunagawa, Masafumi, Funamorto, Hidetoshi Suzuki, Hiromichi Wada, Noriko Asahara, Akira Shimatsu, Hajime Yamakage, Koji Hasegawa, and Tatsuya Morimoto
  • Organizer: International Society of Cardiomyopathies and Heart Failure Congress 2016
  • Place of Presentation: Kyoto
  • Int'l Joint Research
• [Presentation] Nobiletin, a polymethoxy flavonoid, prevents pressure-overload-induced systolic dysfunction in mice (2016)
  • Author(s): Yoichi Sunagawa, Shintaro Ogawahara, Anna Suzuki, Masafumi Funamoto, Ryoga Sakurai, Yasufumi Katanasaka, Tomohiro Asakawa, Toshiyuki Kan, Hiromichi Wada, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: International Society of Cardiomyopathies and Heart Failure Congress 2016
  • Place of Presentation: Kyoto
  • Int'l Joint Research
• [Presentation] Epigenetic Histone Acetylation by p300 are changed from Cardiac Hypertrophy to Heart Failure (2016)
  • Author(s): Masafumi Funamoto, Yoichi Sunagawa, Yasufumi Katanasaka, Kana Shimizu, Yusuke Miyazaki, Hiromichi Wada, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: International Society of Cardiomyopathies and Heart Failure Congress 2016
  • Place of Presentation: Kyoto
  • Int'l Joint Research
• [Presentation] Protein Arginine Methyltransferase 5/Methylosome Protein 50 Complex Inhibits p300 Histone Acetyltransferase Activity and Hypertrophic Gene transcription in Cultured Cardiomyocytes (2015)
  • Author(s): Yusuke Miyazaki, Yasufumi Katanasaka, Yoichi Sunagawa, Hiromichi Wada, Koji Hasegawa and Tatsuya Morimoto
  • Organizer: AHA Scientific Sessions 2015
  • Place of Presentation: Orlando, USA
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Analysis of Novel Target Molecules of Nobiletin, a Potent Therapeutic Agent Against Heart Failure (2015)
  • Author(s): Yoichi Sunagawa, Kehima Hieda, Ryoga Sakurai, Shintaro Ogawahara, Yasufumi Katanasaka, Tomohiro Asakawa, Toshiyuki Kan, Akira Murakami, Hiromichi Wada, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: AHA Scientific Sessions 2015
  • Place of Presentation: Orlando, USA
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] A Transcriptional Co-activator, p300 is Involved in the Epigenetic Gene Activation on Hypertrophic Response Gene Promoters during Cardiomyocyte Hypertrophy (2015)
  • Author(s): Masafumi Funamoto, Yoichi Sunagawa, Yasufumi Katanasaka, Hiromichi Wada、Koji Hasegawa, Tatsuya Morimoto
  • Organizer: 19th Annual Scientific Meeting of the ISCP
  • Place of Presentation: Buenos Aires,Argentina
  • Year and Date: 2015-06-26
  • Int'l Joint Research
• [Presentation] A LIPOPHILIC PITAVASTATIN SUPPRESSES CELL HYPERTROPHY IN CULTURED CARDIOMYOCYTES (2015)
  • Author(s): Yasufumi Katanasaka, Sae Hirano, Yoichi Sunagawa, Ryoga Sakurai, Hidetoshi Suzuki, Hiromichi Wada, Akira Shimatsu, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: Asian Pacific Society of Cardiology Congress 2015
  • Place of Presentation: Abu Dhabi, UAE
  • Year and Date: 2015-04-29
  • Int'l Joint Research
• [Presentation] MEP50 RECRUITS PRMT5 TO p300 AND SUPRESSES p300/GATA4-INDUCED HYPERTROPHIC GENE TRANSCRIPTION (2015)
  • Author(s): Hiroki Wakabayashi, Yasufumi Katanasaka, Yusuke Miyazaki, Ryoga Sakurai, Yoichi Sunagawa, Hiromichi Wada, Koji Hasegawa, Tatsuya Morimoto
  • Organizer: Asian Pacific Society of Cardiology Congress 2015
  • Place of Presentation: Abu Dhabi, UAE
  • Year and Date: 2015-04-29
  • Int'l Joint Research