Molecular mechanism of autonomic regulation of cardiac function

• Project/Area Number: 19390217
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Yokohama City University
• Principal Investigator: ISHIKAWA Yoshihiro Yokohama City University, 医学研究科, 教授 (40305470)
• Co-Investigator(Kenkyū-buntansha): SATO Motohiko 横浜市立大学, 医学部, 准教授 (40292122) ; OKUMURA Satoshi 横浜市立大学, 医学部, 准教授 (60233475) ; 南沢 享 横浜市立大学, 医学研究科, 客員教授 (40257332)
• Co-Investigator(Renkei-kenkyūsha): MINAMISAWA Susumu 横浜市立大学, 医学研究科, 客員教授 (40257332)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2008: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2007: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
• Keywords: 心臓病態学 / 自律神経 / 心機能 / cAMP / カテコラミン / 分子 / 心臓 / 心不全 / ダウンレギュレーション

Research Abstract

心臓に発現するアデニル酸シクラーゼサブタイプの生理的意義を、ノックアウト動物などの遺伝子操作、サブタイプ特異的作動薬などの薬理学的手法を用いて、心機能制御に及ぼす影響を中心に検討した。とくに近年になってcAMPシグナルの新しい下流蛋白として同定されたEpacと呼ばれる制御蛋白を中心にアデニル酸シクラーゼサブタイプとの連関を中心に検討した。本申請は、心機能の最大の制御メカニズムである自律神経調節の分子メカニズムの解明であり、交感神経刺激は心機能の最大の調節因子であることは数十年にわたって認識されてきたが、本研究によって、その分子メカニズムがcAMPによるシグナルネットワークの制御として解明されつつある。

Research Products

• [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, et.al.
  • Journal Title: J Appl Physiol 105 Pages: 173-179
  • Peer Reviewed
• [Journal Article] Sarcalumenin alleviates stress-induced cardiac dysfunction by improving Ca2+ handling of the sarcoplasmic reticulum (2008)
  • Author(s): Shimura M, et.al.
  • Journal Title: Cardiovasc Res 77 Pages: 362-370
• [Journal Article] Epac 1 is upregulated during neointima formation and promotes vascular smooth muscle cell migration (2008)
  • Author(s): Yokoyama U, et.al.
  • Journal Title: Am. J. Physiol. Heart Circ. Physiol 295
• [Journal Article] PGE2-activated Epac promotes neointimal cushin formation of the rat ductus arteriosus by a process distinct from that of PKA (2008)
  • Author(s): Yokoyama U, et.al.
  • Journal Title: J. Biol. Chem 283 Pages: 28702-28709
• [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, et al.
  • Journal Title: J Appl Physiol. 105 Pages: 173-179
  • Peer Reviewed
• [Journal Article] Sarcalumenin alleviates stress-induced cardiac dysfunction by improving Ca2+ handling of the sarcoplasmic reticulum. (2008)
  • Author(s): Shimura M, et al.
  • Journal Title: Cardiovasc Res 77 Pages: 362-370
  • Peer Reviewed
• [Journal Article] Caveolin-3 expression and caveolae are required for isoflurane-induced cardiac protection from hypoxia and ischemia/reperfusion injury. (2008)
  • Author(s): Horikawa Y, et al.
  • Journal Title: J. Mol. Cell. Cardiol 44 Pages: 123-130
  • Peer Reviewed
• [Journal Article] Epacl is upregulated during neointima formation and promotes vascular smooth muscle cell migration. : (2008)
  • Author(s): Yokoyama U, et al.
  • Journal Title: Am. J. Physiol. Heart Circ. Physiol. 295
  • Peer Reviewed
• [Journal Article] A case of giant coronary aneurysm and literature review. (2008)
  • Author(s): Ebina T, et al.
  • Journal Title: J. Cardiol. (in press)
  • Peer Reviewed
• [Journal Article] PGE2-activated Epac promotes neointimal cushin formation of the rat ductus arteriosus by a process distinct from that of PKA (2008)
  • Author(s): Yokoyama U, et al.
  • Journal Title: J. Biol. Chem. 283 Pages: 28702-28709
  • Peer Reviewed
• [Journal Article] Cardiac specific overexpression of caveolin-3 induces endogenous cardiac protection by mimicking ischemic predoncitioning. (2008)
  • Author(s): TsutsumiY, et al.
  • Journal Title: Circulation 118 Pages: 1979-88
  • Peer Reviewed
• [Journal Article] A cyclic AMP pathway selectively required for reward prediction. (2008)
  • Author(s): Kheirbek MA, et al.
  • Journal Title: J. Neurosci 28 Pages: 11401-11408
  • Peer Reviewed
• [Journal Article] Developmental changes in gene expression of Epac and its upregulation in myocardial hypertrophy (2007)
  • Author(s): Ulucan C, Wang X, Baljinnyam E, Bai Y-Z, Okumura S, Sato M, Minamisawa S, Hirotani S, and Ishikawa Y
  • Journal Title: Am.J.Physiol.Heart Circ.Physiol 293
  • Peer Reviewed
• [Journal Article] Dopamine induces apoptosis in young, but not in neonatal, neurons via Ca(2+)-dependent signal, Am (2007)
  • Author(s): Iwatsubo K, Suzuki S, Li C, Tsunematsu T, Nakamura F, Okumura S, Sato M, Minamisawa S, Toya Y, Umemura S, and Ishikawa Y
  • Journal Title: J.Physiol. Cell.Physiol 293
  • Peer Reviewed
• [Journal Article] Isoform-selective regulation of adenylyl cyclase by forskolin derivatives : Prediction of selectivity by computer-based analysis (2007)
  • Author(s): Eguchi H, Iwatsubo K, and Ishikawa Y
  • Journal Title: Letters in Drug Design & Discovery 4 Pages: 434-441
  • Peer Reviewed
• [Journal Article] Disruption of Type 5 adenylyl cyclase enhances desensitization of the cyclic adenosine monophsphate signal and icreases the Akt signal with chronic catecholamine stress (2007)
  • Author(s): Okumura S, Vanter DE, Kurotani R, Bai Y, Gao S, Yuan Z, Iwatsubo K, Ulucan C, Kawabe J, Ghosh K, Vanter FS, and Ishikawa Y
  • Journal Title: Circulation 116 Pages: 1776-1783
  • Peer Reviewed
• [Journal Article] Developmental changes in gene expression of Epac and its upregulation in myocardial hypertrophy. (2007)
  • Author(s): Ulucan C, Wang X, Baljinnyam E, Bai Y-Z, Okumura S, Sato M, Minamisawa S, Hirotani S, and Ishikawa Y
  • Journal Title: Am. J. Physiol. Heart Circ. Physiol. 293
  • Peer Reviewed
• [Journal Article] Dopamine induces apoptosis in young, but not in neonatal, neurons via Ca(2+)-dependent signal. (2007)
  • Author(s): Iwatsubo K, Suzuki S, Li C, Tsunematsu T, Nakamura F, Okumura S, Sato M, Minamisawa S, Toya Y, Umemura S, and Ishikawa Y
  • Journal Title: Am. J. Physiol. Cell. Physiol. 293
  • Peer Reviewed
• [Journal Article] Isoform-selective regulation of adenylyl cyclase by forskolin derivatives: Prediction of selectivity by computer-based analysis. (2007)
  • Author(s): Eguchi H, Iwatsubo K, and Ishikawa Y
  • Journal Title: Letters in Drug Design & Discovery 4 Pages: 434-441
  • Peer Reviewed
• [Journal Article] Interleukin-15 Inhibits Smooth Muscle Cell Proliferation and Hyaluron an Production in Rat Ductus Arteriosus. (2007)
  • Author(s): Iwasaki S, Minamisawa S, Yokoyama U, Akaike T, Quan H, Nagashima Y, Nishimaki S, Ishikawa Y, and Yokota S
  • Journal Title: Pediatr. Res. 62 Pages: 392-398
  • Peer Reviewed
• [Journal Article] Disruption of Type 5 adenylyl cyclase enhances desensitization of the cyclic adenosine monophsphate signal and increases the Akt signal with chronic catecholamine stress. (2007)
  • Author(s): Okumura S, Vatner DE, Kurotani R, Bai Y, Gao S, Yuan Z, Iwatsubo K, Ulucan C, Kawabe J, Ghosh K, Vatner FS, and Ishikawa Y
  • Journal Title: Circulation 116 Pages: 1776-1783
  • Peer Reviewed
• [Journal Article] Maternal vitamin A alters gene profiles and structural maturation of the rat ductus arteriosus. (2007)
  • Author(s): Yokoyama U, Sato Y, Akaike T, Ishida S, Sawada J, Nagao T, Quan H, Jin M, Iwamoto M, Yokota S, Ishikawa Y, and Minamisawa S
  • Journal Title: Physiol. Genomics 31
  • Peer Reviewed
• [Journal Article] 成熟マウス線条体培養法の確立とcAMPシグナルによる細胞死の検討 (2007)
  • Author(s): 鈴木さやか、岩坪耕策、Ulucan Coskun, 常松尚志、石川義弘
  • Journal Title: 日本病態生理学会雑誌 Pages: 26-43
• [Presentation] An Involvement of a Novel G-protein Activator on Hypoxia-Induced Apoptosis of Cardiomyocytes and its Interaction with Connexin 43 (2008)
  • Author(s): Sato M, et.al.
  • Organizer: American Heart Association's Scientific Sessions 2008
  • Place of Presentation: New Orleans
• [Presentation] Activation of Epac1-specific Signaling Protects Heart form Cytokine-Mediated Cardiac Dysfunction through the inhibition of Proinflammatory Cytokine Signaling(Oral presentation) (2008)
  • Author(s): Okumura S, et.al.
  • Organizer: American Heart Association's Scientific Sessions 2008
  • Place of Presentation: New Orleans
• [Presentation] Sarcalumenin plays a critical role in age-dependent reduction in cardiac function and SERCA2a activity (2008)
  • Author(s): Qibin J, et.al.
  • Organizer: Experimental Biology
  • Place of Presentation: San Diego
• [Presentation] An Involvement of a Novel G-protein Activator on Hypoxia-Induced Apoptosis of Cardiomyocytes and its Interaction with Connexin 43. (2008)
  • Author(s): Sato M, et al
  • Organizer: American Heart Association's Scientific Sessions2008
  • Place of Presentation: New Orleans
• [Presentation] Activation of Epacl-specific Signaling Protects Heart from Cytokine-Mediated Cardiac Dysfunction through the inhibition of Proinflammatory Cytokine Sienaling(Oral presentation). (2008)
  • Author(s): Okumura S, et al
  • Organizer: American Heart Association Scientific Sessions2008
  • Place of Presentation: New Orleans
• [Presentation] Sarcalumenin plays a critical role in age-dependent reduction in cardiac function and SERCA2a activity . (2008)
  • Author(s): Qibin J, et al
  • Organizer: Experimental Biology
  • Place of Presentation: San Diego
• [Presentation] Disruption of type 5 adenylyl cyclase preserves cardiac function against chronic catecholamine stress (2007)
  • Author(s): Okumura S, Minamisawa S, Ishikawa Y
  • Organizer: 第11回日本心不全学会
  • Place of Presentation: 東京
• [Presentation] Epac1 promotes intimal cushion formation of the rat ductus arteriosus by enhancing smooth muscle cell migration (2007)
  • Author(s): 赤池徹, 横山詩子, 全紅, 岩本眞理, 石川義弘, 南沢享
  • Organizer: 第71回日本循環器学会総会
  • Place of Presentation: 神戸
• [Presentation] 虚血心筋に発現する新たなG蛋白活性調整因子の同定 (2007)
  • Author(s): 佐藤元彦, 本多崇, ラニアー ステファン,豊田英嗣, シスモウスキー マリー, スマッカ アラン, チリアン ウィリアム, 石川義弘
  • Organizer: 第84回日本生理学会大会
  • Place of Presentation: 大阪
• [Remarks]
  • URL: http://www-user.yokohama-cu.ac.jp/~seiri1/index.html
• [Remarks]
  • URL: http://www-user.yokohama-cu.ac.jp/~seiril/index.html
• [Remarks]
  • URL: http://www-user.yokohama-cu.ac.jp/~seiril/index.html