Molecular mechanisms for cardiac regulation by the autonomic nervous system

• Project/Area Number: 17390234
• 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 Graduate School of Medicine
• Principal Investigator: ISHIKAWA Yoshihiro Yokohama City University, Graduate School of Medicine, Professor, 医学研究科, 教授 (40305470)
• Co-Investigator(Kenkyū-buntansha): MINAMISAWA Susumu Yokohama City University, Graduate School of Medicine, Associate Professor, 医学部, 準教授 (40257332) ; SATO Motohiko Yokohama City University, Graduate School of Medicine, Associate Professor, 医学部, 準教授 (40292122) ; OKUMURA Satoshi Yokohama City University, Graduate School of Medicine, Associate Professor, 医学部, 助手 (60233475) ; IWATSUBO Kousaku Yokohama City University, Graduate School of Medicine, Assistant Professor (90363796)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥15,300,000 (Direct Cost: ¥15,300,000); Fiscal Year 2006: ¥7,400,000 (Direct Cost: ¥7,400,000); Fiscal Year 2005: ¥7,900,000 (Direct Cost: ¥7,900,000)
• Keywords: autonomic nervous sytem / catecholamine / heart / cAMP / congestive heart failure / downregulation / 交感神経 / アデニル酸シクラーゼ / 遺伝子操作

Research Abstract

Sympathetic nervous system is a major mechanism of regulating cardiac function. Catecholamines released from the synaptic terminal bind to catecholamine receptors, leading to the activation of the stimulatory G protein and then adenylyl cyclase, leading to increased cardiac contractility and heart rate. There are at least 9 subtypes for adenylyl cyclase; type 5 is known to be the major subtype expressed in the heart. This isoform has been known to be developmentally regulated; its expression is relatively low at birth, but increased with aging. We have demonstrated that there are multiple mechanism to regulate this adenylyl cyclase subtype through distinct mechanisms of regulation. In the current research, we have investigated the role of this adenylyl cyclase subtype in not only regulating cardiac function but regulating and inducing cardiac myocyte apoptosis. We examined its role under chronic catecholamine stimulation. In order to examine the role of this adenylyl cyclase subtype, w e developed a mouse line in which the expression of this subtype was deleted. Basal cardiac function was relatively maintained in AC5KO, however, after chronic isoproterenol infusion by the use of osmotic minipump, cardiac function in wild type mice deteriorated significantly while that in AC5KO remained relatively conserved. When the number of apoptotic cardiac myocytes were counted, we found that the number was significantly decreased in AC5KO. Furthermore, the activation of Ala was significantly increased in AC5KO. These findings have suggested that the deletion of type 5 adenylyl cyclase plays a beneficial role in protecting the heart from chronic catecholamine stress. Together with recent development of compounds that can inhibit this adenylyl cyclase subtype in a subtype-specific manner, it is tentative to propose that the use of such type 5 adenylyl cyclase inhibitor may serve as an alternate to protect the heart under various pathophysiological condition where catecholamine stress is increased.

Research Products

• [Journal Article] Multiple transcripts of Ca2+ channel subunits and a novel spliced variant of alpha1C subunit in the rat ductus arteriosus (2006)
  • Author(s): Yokoyama U, Minamisawa S, Adachi-Akahane S, Akaike T, Naguro I, Funakoshi K, Iwamoto M, Nakagome M, Uemura N, Hori H, Yokota S, Ishikawa Y
  • Journal Title: Am. J. Physiol 290
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Caveolin regulates microtubule polymerization in the vascular smooth muscle cells (2006)
  • Author(s): Kawabe J, Okumura S, Nathanson MS, Hasebe N, Ishikawa Y
  • Journal Title: Biochem. Biophys. Res. Commun. 342 Pages: 164-169
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Caveolin-3inhibits growth signal in cardiac myoblasts in a Ca2+-dependent manner. (2006)
  • Author(s): Fujita T, Otsu K, Oshikawa J, Hori H, Minamisawa s, Umemure S, Kitamura H, Ito T, Ishikawa Y
  • Journal Title: J. Cell. Mol. Med. 10 Pages: 216-224
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Post-transcriptional down-regulation of sarcolipin mRNA by triodothyronine in the atrial myocardium. (2006)
  • Author(s): Minamisawa S, Umemura N, Sato Y, SatYokoyama U, Yamaguchi T, Inoue K, Nakagome M, Bat Y, Hori H, Simizu M, Mochizuki S, Ishikawa Y
  • Journal Title: FEBS Lett. 580 Pages: 2247-2253
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Chronic activation of the prostaglandin receptor EP4 promotes hyaluronan-mediated neointimal formation in the ductus arteriosus. (2006)
  • Author(s): Yokoyama U, Minamisawa S, Hong Q, Segi-Nishida E, Ghatak S, Iwasaki S, Iwamoto M, Misra S, Tamura K, Hori H, Yokota S, Tool BP, Sugimoto Y, Ishikawa Y
  • Journal Title: J. Clin. Invest 116 Pages: 3026-3034
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Multiple transcripts of Ca2+ channel subunits and a novel spliced variant of alphalC subunit in the rat ductus arteriosus (2006)
  • Author(s): Yokoyama U, Minamisawa S, Adachi-Akahane S, Akaike T, Naguro I, Funakoshi K, Iwamoto M, Nakagome M, Uemura N, Hori H, Yokota S, Ishikawa Y
  • Journal Title: Am. J. Physiol 290
• [Journal Article] Caveolin-3inhibits growth signal in cardiac myoblasts in a Ca2+-dependent manner. (2006)
  • Author(s): fujita T, Otsu K, Oshikawa J, Hori H, Minamisawa S, Umemura S, Kitamura H, Ito T, Ishikawa Y
  • Journal Title: J. Cell. Mol. Med. 10 Pages: 216-224
• [Journal Article] Impaired Ca2+ store functions in skeletal and cardiac muscle cells from sarcalumenin-deficient mice. (2005)
  • Author(s): Yoshida M, Minamisawa S, Shimura M, Komazaki S, Kume H, Zhang M, Matsumura K, Nishi M, Saito M, Saeki Y, Ishikawa Y, Yanagisawa T, Takeshima H.
  • Journal Title: J Biol Chem 280 Pages: 3500-3506
• [Journal Article] Congenital semilunar valvulogenesis defect in mice deficient in phospholipase Cε (2005)
  • Author(s): Tadano M, Edamatsu H, Minamisawa S, Yokoyama U, Ishikawa Y, Suzuki N, Saito H, Wu D, Masago-Toda M, Yamawaki-Kataoka Y, Setsu T, Terashima T, Maeda S, Satoh T, Kataoka T
  • Journal Title: Mol Cell Biol 25(6) Pages: 2191-2199
• [Journal Article] Mechanical stress-dependent transcriptional regulation of the sarcolipin gene in the rodent atrium (2005)
  • Author(s): Shimura M, Minamisawa S (correspondence), Yokoyama U, Umemura S, Ishikawa Y.
  • Journal Title: Biochem Biophys Res Commun 334 Pages: 861-866