Role of Epac in cardiac fibrosis and its clinical application for heart failure

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591087
• 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: Tsurumi University
• Principal Investigator: OKUMURA Satoshi 鶴見大学, 歯学部, 教授 (60233475)
• Co-Investigator(Kenkyū-buntansha): SATO Motohiko 愛知医科大学, 医学部, 教授 (40292122)
• Project Period (FY): 2011 – 2013
• Keywords: シグナル伝達 / 循環器高血圧 / サイクリックAMP / 心不全 / 遺伝子改変マウス

Research Abstract

In order to examine the role of Epac1 (exchange protein directly activated by cyclic AMP) on cardiac fibrosis, chronic isoproterenol (ISO) infusion (60mg/kg/day for 7 days) was performed in Epac1-null mice (Epac1KO) and wild-type controls (WT). Cardiac fibrosis was significantly inhibited in Epac1KO, compared to WT. In order to examine the mechanism, we examined the role of Epac1 in the following 3 steps : Step-1) Production of collagen fiber Step-2) Cross-linking of collagen fiber by lysyl oxidase (LOX) Step-3) Degradation of collagen fiber by matrix mettaloproteinase (MMT). Our data in this study shows that cardiac fibrosis was reduced through the inhibition of step-3.

Research Products

• [Journal Article] Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses (2014)
  • Author(s): Okumura S, Fujita T, Cai W, Jin M, Namekata I, Mototani Y, Jin H, Ohnuki Y, Tsuneoka Y, Kurotani R, Suita K, Kawakami Y, Hamaguchi S, Abe T, Kiyonari H, Tsunematsu T, Bai Y, Suzuki S, Hidaka Y, Umemera M, Ichikawa Y, Yokoyama U, Sato m, Ishikawa F, Izumi-Nakaseko H, Adachi-Akahane S, Tanaka H, Ishikawa Y
  • Journal Title: J Clin Invest Volume: 124 Pages: 2785-2801
  • Peer Reviewed
• [Journal Article] Protection of cardiomyocytes from the hypoxia-mediated injury by a peptide targeting the G-protein signaling 8 (2014)
  • Author(s): Sato M, Hiraoka M, Sakima M, Yamane Y, Fujita T, Okumura S, Ishikawa Y
  • Journal Title: PLoS One Volume: 14 Pages: e91980
  • Peer Reviewed
• [Journal Article] (2014)
  • Author(s): Sato I, Umemura M, Mitsudo K, Kioi M, Nakashima H, Iwai T, Feng X, Oda K, Miyajima A, Makino A, Iwai M, Fujita T, Yokoyama U, Okumura S, Sato M, Eguchi H, Tohnai I, Ishikawa Y
  • Journal Title: J Physiol Sci Volume: 64 Pages: 177-183
  • Peer Reviewed
• [Journal Article] Effects of the masticatory demand on the rat mandibular development (2014)
  • Author(s): Hichijo N, Kawai N, Mori H, Sano R, Ohnuki Y, Okumura S, langenbach GE, Tanaka E
  • Journal Title: J Oral Rehabil Volume: (in press)
  • Peer Reviewed
• [Journal Article] Effect of protein kinase A on the phosphorylation status and transverse stiffness of cardiac myofibrils (2013)
  • Author(s): Ohnuki Y, Yamada T, Mototani Y, Umeki D, Shiozawa K, Fujita T, Saeki Y, Okumura S
  • Journal Title: J Pharamacol Sci Volume: 123 Pages: 279-283
  • Peer Reviewed
• [Journal Article] Role of masseter muscleβ2-adrenergic signaling in regulation of muscle activity, myosin heavy chain transition, and hypertrophy (2013)
  • Author(s): Ohnuki Y, Umeki D, Cai W, Kawai N, Mototani Y, Shiozawa K, Jin HL, Fujita T, Tanaka E, Saeki Y, Okumura S
  • Journal Title: J Pharmacol Sci Volume: 123 Pages: 36-46
  • Peer Reviewed
• [Journal Article] Effects of chronic Akt/mTOR inhibition by rapamycin on mechanical overload-induced hypertrophy and myosin heavy chain transition in masseter muscle (2013)
  • Author(s): Umeki D, Ohnuki Y, Mototani Y, Shiozawa K, Fujita T, Nakamura Y, Saeki Y, Okumura S
  • Journal Title: J Pharmacol Sci Volume: 122 Pages: 278-288
  • Peer Reviewed
• [Journal Article] Pharmacological stimulation of type 5 adenylyl cyclase stabilizes heart rate under both microgravity and hypergravity induced by parabolic flight (2012)
  • Author(s): Bai Y, Tsunematsu T, Jiao Q, Ohnuki Y, Mototani Y, Shiozawa K, Jin M, Cai W, Jin HL, Fujita T, Ichikawa Y, Suita K, Kurotani R, Yokoyama U, Sato M, Iwatsubo K, Ishikawa Y, Okumura S
  • Journal Title: J Pharmacol Sci Volume: 119 Pages: 381-389
  • Peer Reviewed
• [Journal Article] Inhibition of EP4 signaling attenuate aortic aneurysm formation (2012)
  • Author(s): Yokoyama U, Ishiwata R, Jin MH, Kato Y, Suzuki O, Jin H, Ichikawa Y, Kumagaya S, Katayama Y, Fujita T, Okumura S, Sato M, Sugimoto Y, Aoki H, Suzuki S, Masuda M, Minamisawa S, Ishikawa Y
  • Journal Title: Plos One Volume: 7 Pages: e36724
  • Peer Reviewed
• [Journal Article] Inhibition of phosphodiesterase type 3 dilates the rat ductus arteriosus without inducing intimal thickening (2012)
  • Author(s): Ichikawa Y, Yokoyama U, Iwamoto M, Oshikawa J, Okumura S, Sato M, Yokota S, Masuda M, Asou T, Ishikawa Y
  • Journal Title: Circ J Volume: 76 Pages: 2456-2464
  • Peer Reviewed
• [Journal Article] Effects of ascorbic acid on reactive oxygen species production in chemotherapy and hyperthermia inprostate cancer cell (2012)
  • Author(s): Fukumura H, Sato M, Kezuka K, Sato I, Feng X, Okumura S, Fujita T, Yokoyama U, Eguchi H, Ishikawa Y, Saito T
  • Journal Title: J Physiol Sci Volume: 62 Pages: 251-257
  • Peer Reviewed
• [Journal Article] (2012)
  • Author(s): Iwatsubo K, Brav C, Uechi M, Baljinnyam E, Nakamura T, Umemura M, Lai L, gao S, Yan L, Zhao X, Park M, Qiu H, Okumura S, Iwatsubo M, Vatner DE, Vatner SF, Ishikawa Y
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: 302 Pages: H2622-H2628
  • Peer Reviewed
• [Journal Article] Secretoglobin 3A2 supresses bleomycin-induced pulmonary fibrosis by transforming growth factorβsignaling down-regulation (2011)
  • Author(s): Kurotani R, Okumura S, Matsubara T, Yokoyama U, Buckley JR, Tomita T, Kezuka K, Nagano T, Esposito D, Taylor TE, Gillette WK, Ishikawa Y, Abe H, Ward JM, Kimura S
  • Journal Title: J Biol Chem Volume: 286 Pages: 19682-19692
  • Peer Reviewed
• [Journal Article] Identification of transforming factor E3 (TFE3) as a receptor-independent activator of Gα16 (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: 286 Pages: 17766-17776
  • Peer Reviewed
• [Journal Article] The role 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 Volume: 12 Pages: 526-532
  • Peer Reviewed
• [Presentation] Vidarabine, a selective cardiac adenylyl cyclase inhibitor, prevents ventricular arrhythmia in Calsequestrin 2 knockout mouse (2014)
  • Author(s): Suita K, Okumur a S, et al.
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 20140321-23
• [Presentation] Vidarabine, a selective cardiac adenylyl cyclase inhibitor, prevents ventricular arrhythmia in Calsequestrin 2 knockout mouse (2014)
  • Author(s): Suita K, Okumur a S, et al.
  • Organizer: 第91回日本生理学会大会
  • Place of Presentation: 鹿児島大学
  • Year and Date: 20140316-18
• [Presentation] Roles of Epac in masseter muscle hypertrophy induced by chronic stimulation of beta 2 adorenoreceptor (2014)
  • Author(s): Ohnuki Y, Okumura S, et al.
  • Organizer: 第91回日本生理学会大会
  • Place of Presentation: 鹿児島大学
  • Year and Date: 20140316-18
• [Presentation] George E Brown Memor ial Lecture and Molecular Mechanism of Hear t Failure (2012)
  • Author(s): Okumur a S, et al
  • Organizer: Disruption of Epac1 decreases phosphorylation of phospholamban and protects the heart against stress Amer ican Hear t Association Scientifc Scission 2012
  • Place of Presentation: Los Angeles in USA(Oral presentation)
  • Year and Date: 20121103-07
• [Presentation] Epac activation protects heart from interleukin-6-induced cardiac dysfunction by inhibiting STAT/iNOS signaling (2011)
  • Author(s): Okumur a S,, et al.
  • Organizer: American Heart Association Scientific Sessions 2011
  • Place of Presentation: Orlando in USA(Oral presentation)
  • Year and Date: 20111112-16
• [Presentation] Disruption of Epac1 protects heart from catecholamine-mediated cardiac fibrosis (2011)
  • Author(s): Okumura S, et al.
  • Organizer: 第75回日本循環器学会学術集会
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 20110803-04
• [Presentation] Effects of beta-2 adrenoceptor agonists on function and phenotype of rat masseter muscle
  • Author(s): Ohnuki Y, Okumura S, et al.
  • Organizer: 第51回歯科基礎医学会総会
  • Place of Presentation: 岡山大学
  • Year and Date: 00000920-23
• [Book] 歯科基礎生理学第6版(共著) (2014)
• [Remarks] 鶴見大学 歯学部 生理学講座
  • URL: http://dent.tsurumi-u.ac.jp/guide/course/basic/331
• [Remarks] 横浜市立大学 医学部 循環制御医学
  • URL: http://www-user.yokohama-cu.ac.jp/~seiri1/
• [Remarks] 愛知医科大学 医学部 生理学
  • URL: http://www.aichi-med-u.ac.jp/physio2/
• [Patent(Industrial Property Rights)] ビダラビンによる心房細動治療 (2012)
  • Inventor(s): 石川義弘、奥村 敏、吹田憲治
  • Industrial Property Rights Holder: 横浜市立大学
  • Industrial Property Rights Type: 国際特許
  • Industrial Property Number: PCT/JP2012/069540
  • Filing Date: 2012-08-01
• [Patent(Industrial Property Rights)] アデニル酸シクラーゼの活性調節剤 (2011)
  • 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、横浜国立大学
  • Industrial Property Rights Type: 国際特許
  • Industrial Property Number: PCT/JP2011/074098
  • Filing Date: 2011-10-20
• [Patent(Industrial Property Rights)] ビダラビンによる心房細動治療 (2011)
  • Inventor(s): 石川義弘、奥村 敏、吹田憲治
  • Industrial Property Rights Holder: 横浜市立大学
  • Industrial Property Rights Type: 国内特許
  • Industrial Property Number: 特願2011-222421
  • Filing Date: 2011-10-07