To examine the role of Epac, a new beta-adrenergic signaling molecule, for the development of heart failure

• Project/Area Number: 20590871
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Yokohama City University
• Principal Investigator: OKUMURA Satoshi Yokohama City University, 医学部, 准教授 (60233475)
• Co-Investigator(Kenkyū-buntansha): SATO Motohiko 横浜市立大学, 医学部, 准教授 (40292122) ; KUROTANI Reiko 横浜市立大学, 医学研究科, 特任助教 (00453043)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: サイクリックAMP / シグナル伝達 / 循環器・高血圧 / 心不全 / 遺伝子改変マウス

Research Abstract

It is well known that sympathetic and thus catecholamine signal is activated thereafter to compensate cardiac dysfunction. The mechanism of such compensation by catecholamine has been traditionally understood as PKA-mediated enforcement of cardiac contractility. We hypothesized that Epac, a new target of cAMP signal that functions independently from PKA, also plays a key role. Epac1 inhibited the Jak-STAT pathway and iNOS protein in the heart in response via IL-6. Activation of the cAMP/Epac pathway protected the heart against cytokine-induced cardiac dysfunction, suggesting a new role of catecholamine signal in compensating cardiac dysfunction in endotoxemia.

Research Products

• [Journal Article] Secretoglobin 3A2 suppresses bleomycin-induced pulmonary fibrosis by TGF・・signaling down-regulation. (2011)
  • Author(s): Kurotani R, Okumura S, Matsubara T, Yokoyama U, Buckley JR, Tomita T, Kezuka K, Nagao T, Esposito D, Tayler TE, Gillette WK, Ishikawa Y, Abe H, Ward JM, Kimura S
  • Journal Title: J Biol Chem 386 Pages: 19682-19692
  • Peer Reviewed
• [Journal Article] The roles of cytochrome P450 in ischemic heart disease. (2011)
  • Author(s): Sato M, Yokoyama U, Fujita T, Okumura S, Ishikawa Y
  • Journal Title: Curr Drug Metab
  • Peer Reviewed
• [Journal Article] Identification of transcriptional factor E3 (TFE3) as a receptor-independent activator of G・16 : Gene regulation by nuclear G・ subunit and its activator. (2011)
  • Author(s): Sato M, Hiraoka M, Suzuki H, Bai Y, Kurotani R, Yokoyama U, Okumura S, Cismowski MJ, Lanier SM, Ishikawa Y
  • Journal Title: J Biol Chem 286 Pages: 17766-17776
  • Peer Reviewed
• [Journal Article] Identification of transcriptional factor E3 (TFE3) as a receptor-independent activator of Gα16 : Gene regulation by nuclear Gα subunit and its activator (2011)
  • Author(s): Sato M, Hiraoka M, Suzuki H, Bai Y, Kurotani R, Yokoyama U, Okumura S, Cismowski MJ, Lanier SM, Ishikawa Y
  • Journal Title: J Biol Chem Volume: (In press)
  • Peer Reviewed
• [Journal Article] The roles of cytochrome P450 in ischemic heart disease (2011)
  • Author(s): Sato M, Yokoyama U, Fujita T, Okumura S, Ishikawa Y
  • Journal Title: Cure Drug Metab Volume: (In press)
  • Peer Reviewed
• [Journal Article] Secretoglobin 3A2 suppresses bleomycin-induced pulmonary fibrosis by TGFβ signaling down-regulation (2011)
  • Author(s): Kurootani R, Okumura S, Matsubara T, Yokoyama U, Buckley JR, Tomito T, Kezuka K, Nagao T, Esposito D, Tayler TE, Gillette WK, Ishikawa Y, Abe H, Ward JM, Kimura S
  • Journal Title: J Biol Chem Volume: (In press)
  • Peer Reviewed
• [Journal Article] Differential roles of Epac in regulating cell death in neuronal and myocardial cells. (2010)
  • Author(s): Suzuki S, Yokoyama U, Abe T, Kiyonari H, Yamashita N, Kato Y, Kurotani R, Sato M, Okumura S, Ishikawa Y
  • Journal Title: J Biol Chem Pages: 24248-24259
  • Peer Reviewed
• [Journal Article] Differential regulation of vascular tone and remodeling via stimulation of type 2 and type 6 adenylyl cyclases in the ductus arteriosus. (2010)
  • Author(s): Yokoyama U, Minamisawa S, Katayama A, Tang T, Suzuki S, Iwatsubo K, Iwasaki S, Kurotani R, Okumura S, Sato M, Yokota S, Hammond HK, Ishikawa Y
  • Journal Title: Circ Res 106 Pages: 1882-1892
  • Peer Reviewed
• [Journal Article] Caveolin gene transfer improves glucose metabolism in diabetic mice. (2010)
  • Author(s): Otsu K, Toya Y, Oshikawa J, Kurotani R, Yazawa T, Sato M, Yokoyama U, Umemura S, Minamisawa S, Okumura S, Ishikawa Y
  • Journal Title: Am J Physiol Cell Physiol 298
  • Peer Reviewed
• [Journal Article] Differential regulation of vascular tone and remodeling via stimulation of type 2 and type 6 adenylyl cyclases in the ductus arteriosus (2010)
  • Author(s): Yokoyama U, Minamisawa S, Katayama A, Tang T, Suzuki S, Iwatsubo K, Iwasaki S, Kurotani R, Okumura S, Sato M, Yokota S, Hammond HK, Ishikawa Y
  • Journal Title: Circ Res Volume: 106 Pages: 1882-1892
  • Peer Reviewed
• [Journal Article] Differential roles of Epac in regulating cell death in neuronal and myocardial cells (2010)
  • Author(s): Suzuki S, Yokoyama U, Abe T, Kiyonari H, Yamashita N, Kato Y, Kurotani R, Sato M, Okumura S, Ishikawa Y
  • Journal Title: J Biol Chem Volume: 285 Pages: 24248-24259
  • Peer Reviewed
• [Journal Article] New aspects for the treatment of cardiac diseases based on diversity of functional controls on cardiac muscles : effects of targeted disruption of the type 5 adenylyl cyclkase gene (Review). (2009)
  • Author(s): Okumura S, Suzuki S, Ishikawa Y
  • Journal Title: J Phramacol Sci 109 Pages: 354-359
  • Peer Reviewed
• [Journal Article] Activator of G protein signaling 8 (AGS8) is required for hypoxia-induced apoptosis of cardiomyocytes : role of G・・ and connexin 43 (CX43). (2009)
  • Author(s): Sato M, Jiao Q, Honda T, Kurotani R, Toyota E, Okumura S, Takeya T, Minamisawa S, Lanier SM, Ishikawa Y
  • Journal Title: J Biol Chem 284 Pages: 31431-31440
• [Journal Article] Caveolin gene transfer improves glucose metabolism in diabetic mice (2009)
  • Author(s): Otsu K, Toya Y, Oshikawa J, Kurotani R, Yazawa T, Sato M, Yokoyama U, Umemura S, Minamisawa S, Okumura S, Ishikawa Y
  • Journal Title: Am J Physiol Cell physiol 298
  • Peer Reviewed
• [Journal Article] Actibator of G protein signaling 8(AGS8)is required for hypoxia-induced apoptosis of cardiomyocytes : role of Gβγ and connexin 43(CX43) (2009)
  • Author(s): Sato M, Jiao Q, Honda T, Kurotani R, Toyota E, Okumura S, Takeya T, Minamisawa S, Lanier SM, Ishikawa Y
  • Journal Title: J Biol Chem 284 Pages: 31431-31440
  • Peer Reviewed
• [Journal Article] New aspects for the treatment of cardiac diseases based on the diversity of functional controls on cardiac muscles : effects of targeted disruption of the type 5 adenylyl cyclase gene (2009)
  • Author(s): Okumura S, Suzuki S, Ishikawa Y
  • Journal Title: J Pharmacol Sci 109 Pages: 354-359
  • NAID: 10025735009
  • Peer Reviewed
• [Journal Article] Type 5 adenylyl cyclase plays a major role in stabilizing heart rate in response to microgravity induced by parabolic flight. (2008)
  • Author(s): Okumura S, Tsunematsu T, Bai Y, Jiao Q, Ono S, Suzuki S, Kurotani R, Sato M, Umemura S, Minamisawa S, Ishikawa Y
  • Journal Title: J Apply Physiol 105 Pages: 173-179
  • Peer Reviewed
• [Journal Article] Type 5 adenylyl cyclase plays a major role in stabilizing heart rate in response to microgravity induced by parabolicflight (2008)
  • Author(s): Okumura S, et al.
  • Journal Title: J Apply Physiol 105 Pages: 173-179
  • Peer Reviewed
• [Presentation] Activation of Epac Signaling Protects Cardiac Myocyte from Cytokine-mediated Cardiac Dysfunction through the Inhibition of Proinflamatory Cytokine Signaling (2011)
  • Author(s): Fumika Kawamata, Satoshi Okumura, Utako Yokoyama, Yoshihiro Ishikawa
  • Organizer: 第88回日本生理学会大会
• [Presentation] Activation of Epac signaling protects cardiac myocyte from cytokine-mediated cardiac dysfunction through the inhibition of proinflammatory cytokine signaling (2011)
  • Author(s): Fumika Kawamata, Satoshi Okumura, Utako Yokoyama, Yoshihiro Ishikawa
  • Organizer: The 88^<th> Annual Meeting of the Physiological Society of Japan
  • Place of Presentation: Yokohama in Japan(誌上開催)
• [Presentation] Pharamacological activation of type 5 adenyly1 cyclase stabilizes heart rate under microgravity induced by parabolic flight (2010)
  • Author(s): Okumura S, Bai Y, Tsunematsu T, Jin M, Jiao Q, Suzuki S, Kurotani R, Yokoyama U, Sato M, Iwatsubo K, Ishikawa Y
  • Organizer: The 74^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Kyoto in Japan
  • Year and Date: 2010-03-07
• [Presentation] Novel transcription regulation in the hypertrophied myocardium via nuclear G・16 subunit activator G-protein signaling (AGS) (2010)
  • Author(s): Motohiko Sato, Masaharu Hiraoka, Hiroko Suzuki, Bay Yunzhe, Satoshi Okumura, Mary J. Cismowski, Stephen M. Lanier, Yoshihiro Ishikawa
  • Organizer: American Heart Association Scientific Sessions
  • Place of Presentation: Chicago
• [Presentation] Pharmacological activation of type 5 adenylyl cyclase stabilizes heart rate under microgravity induced by parabolic flight (2010)
  • Author(s): Satoshi Okumura, Yunzhe Bai, Takashi Tsunematsu, Meihua Jin, Qibin Jiao, Sayaka Suzuki, Reiko Kurotani, Utako Yokoyama, Motohiko, Sato, Kousaku Iwatsubo, Yoshihiro Ishikawa
  • Organizer: 第74回日本循環器学会学術集会
  • Place of Presentation: 京都
• [Presentation] Disruption of Epac1 Gene Preserves Cardiac Function against Pressure Overload and Chronic Catecholamine Stress (2010)
  • Author(s): Meihua Jin, Satoshi Okumura, Wenqian Cai, Yuko Hidaka, Reiko Kurotani, Utako Yokoyama, Motohiko Sato, Yoshihiro Ishikawa
  • Organizer: 第87回日本生理学会大会
  • Place of Presentation: 岩手
• [Presentation] Novel transcription regulation in the hypertrophied myocardiumvia nuclear Gα16 subunit and activator of G-protein signaling (AGS) (2010)
  • Author(s): Motohiko Sato, Masaharu Hiraoka, Hiroko Suzuki, Bai Yunzhe, Satoshi Okumura, Mary J.Cismowski, Stephen M.Lanier, Yoshihiro Ishikawa
  • Organizer: American Heart Association Scientific Scission 2010
  • Place of Presentation: Chicago in USA
• [Presentation] Epac1 protects heart from lopopolysaccharide-induced cardiac dysfunction by inhibiting the toll-like receptor 4 signaling pathway (2009)
  • Author(s): Okumura S, Jin M, Bai Y, Suzuki S, Xuan X, Cai W, Hidaka Y, Kurotani R, Yokoyama U, Ishikawa Y
  • Organizer: American heart Association Scientific Scission 2009
  • Place of Presentation: Orlando in USA
  • Year and Date: 2009-11-17
• [Presentation] Activation of Epacl-specific Signaling Protects Heart from Cytokine-Mediated Cardiac Dysfunction through the inhibition of Proinflammatory Cytokine Signaling (Featured Research Scission) (2009)
  • Author(s): Okumura S, Suzuki S, Yunzhe B, Meihua J, Hidaka Y, Kurotani R, Ishikawa Y
  • Organizer: The 73^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Osaka
  • Year and Date: 2009-03-21
• [Presentation] Epac1 Protects Heart From Lipopolysaccharide-induced Cardiac Dysfunction By Inhibiting The Toll-like Receptor 4 Signaling Pathway (2009)
  • Author(s): Satoshi Okumura, Meihua Jin, Yunzhe Bai, Sayaka Suzuki, Xuezhe Xuan, Wenqian Cai, Yuko Hidaka, Reiko Kurotani, Utako Yokoyama, Yoshihiro Ishikawa
  • Organizer: American Heart Association Scientific Sessions
  • Place of Presentation: Orlando
• [Presentation] Activation of Epac1-specific signaling protects heart from cytokine-mediated cardiac dysfunction through the inhibition of proinflammatory cytokine signaling (2009)
  • Author(s): Satoshi Okumura, Sayaka Suzuki, Yunzhe Bai, Meihua Jin, Reiko Kurotani, Yoshihiro Ishikawa
  • Organizer: 第73回日本循環器学会学術集会
  • Place of Presentation: 大阪
• [Presentation] Activation of Epacl-specific Signaling Protects Heart from Cytokine-Mediated Cardiac Dysfunction through the inhibition of Proinflammatory Cytokine Sienaline (2008)
  • Author(s): Okumura S, Suzuki S, Yunzhe B, Meihua J, Kurotani R, Ishikawa Y
  • Organizer: American Heart Association Scientific Sessions 2008
  • Place of Presentation: New Orleans in USA
  • Year and Date: 2008-11-10
• [Presentation] Activation of Epac1-specific Signaling Protects Heart from Cytokine-Mediated Cardiac Dysfunction through the inhibition of Proinflammatory Cytokine Signaling. (2008)
  • Author(s): Satoshi Okumura, Sayaka Suzuki S, Yunzhe Bai, Meihua J, in, Reiko Kurotani, Yoshihiro Ishikawa
  • Organizer: American Heart Association Scientific Sessions
  • Place of Presentation: New Orleans
• [Remarks] 横浜市立大学循環制御医学ホームページ
• [Remarks] 横浜市立大学循環制御医学ホームページ
• [Remarks]
  • URL: http://www-user.yokohama-cu.ac.jp/~seiri1/index.html
• [Patent(Industrial Property Rights)] アデニル酸シクラーゼの活性調節剤 (2010)
  • Inventor(s): 石川義弘、奥村 敏、星野雄二郎、井上誠一
  • Industrial Property Rights Holder: 横浜市立大学(60%),横浜国立大学(40%)
  • Industrial Property Number: 2010-240301
  • Filing Date: 2010-10-27
• [Patent(Industrial Property Rights)] アデニル酸シクラーゼの活性調節剤 (2010)
  • Inventor(s): 石川義弘、奥村敏、星野雄二郎、井上誠一
  • Industrial Property Rights Holder: 横浜市立大学(60%),横浜国立大学(40%)
  • Industrial Property Number: 2010-240301
  • Filing Date: 2010-10-27