The study investigating the effects of non-neuronal cardiac cholinergic system on intervention of the metabolic remodelling

• Project/Area Number: 25460333
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Nippon Medical School
• Principal Investigator: Kakinuma Yoshihiko 日本医科大学, 医学(系)研究科(研究院), 教授 (40233944)
• Co-Investigator(Renkei-kenkyūsha): SATO TAKAYUKI 高知大学, 教育研究部医療学系, 教授 (90205930)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: アセチルコリン / 心臓 / 非神経性心臓コリン作動系 / 非神経性コリン作働系 / 遺伝子改変マウス / 心機能 / 心室筋 / エネルギー代謝 / 心筋

Outline of Final Research Achievements

In vivo biological functions of a non-neuronal cardiac cholinergic system (NNCCS) was investigated using the heart-specific ChAT tg mice (ChAT tgm), in which choline acetyltransferase (ChAT) gene was overexpressed under the control of an alpha MHC promoter. ChAT tgm showed comparable hemodynamic parameters and cardiac functions, compared with WT mice. ChAT tgm was resistant against myocardial infarction with a remarkably improved survival rate, more intact myocardium in the infarcted area as well as enhanced angiogenesis, and more glucose uptake in cardiomyocytes, compared with WT mice. Isolated ChAT tgm hearts showed a longer beating period even in the global ischemia and faster recovery of beating after ischemia canceled. These results suggest that NNCCS can be a therapeutic target against cardiovascular diseases.

Research Products

• [Journal Article] Chronic restraint stress triggers dopaminergic and noradrenergic neurodegeneration: Possible role of chronic stress in the onset of Parkinson's disease (2016)
  • Author(s): Sugama S, Sekiyama K, Kodama T, Takamatsu Y, Takenouchi T, Hashimoto M, Conti B, Kakinuma Y
  • Journal Title: Brain Behav Immun Volume: 51 Pages: 39-46
  • DOI: 10.1016/j.bbi.2015.08.015
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Remote ischemic preconditioning with a specialized protocol activates the non-neuronal cardiac cholinergic system and increases ATP content in the heart. (2015)
  • Author(s): Oikawa S, Mano A, Takahashi R, Kakinuma Y.
  • Journal Title: Int Immunopharmacol. Volume: 29 Issue: 1 Pages: 181-184
  • DOI: 10.1016/j.intimp.2015.06.004
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Future perspectives of a cardiac non-neuronal acetylcholine system targeting cardiovascular diseases as an adjunctive tool for metabolic intervention. (2015)
  • Author(s): Kakinuma Y.
  • Journal Title: Int Immunopharmacol Volume: 29 Issue: 1 Pages: 185-188
  • DOI: 10.1016/j.intimp.2015.05.029
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Nicotinic receptor-dependent and -independent effects of galantamine, an acetylcholinesterase inhibitor, on the non-neuronal acetylcholine system in C2C12 cells. (2015)
  • Author(s): Oikawa S, Mano A, Iketani M, Kakinuma Y
  • Journal Title: Int Immunopharmacol Volume: 29 Issue: 1 Pages: 31-35
  • DOI: 10.1016/j.intimp.2015.04.057
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Impaired miR449a-induced downregulation of Crhr1 expression in low-birth-weight rats. (2015)
  • Author(s): Nemoto T, Kakinuma Y, Shibasaki T.
  • Journal Title: J Endocrinol Volume: 224 Issue: 2 Pages: 195-203
  • DOI: 10.1530/joe-14-0537
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Restraint-induced glucocorticoid receptor downregulation is dysregulated in high fat diet-fed rats likely from impairment of miR-142-3p expression in the hypothalamus and hippocampus. (2015)
  • Author(s): Nemoto T, Kakinuma Y, Shibasaki T.
  • Journal Title: Am J Life Sciences Volume: 3 Issue: 3 Pages: 24-30
  • DOI: 10.11648/j.ajls.s.2015030302.15
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Concept of a Nonneuronal Cardiac Cholinergic System (2014)
  • Author(s): Kakinuma Y
  • Journal Title: Journal of Nippon Medical School Volume: 81 Issue: 5 Pages: 296-297
  • DOI: 10.1272/jnms.81.296
  • NAID: 130004703880
  • ISSN: 1345-4676, 1347-3409
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Nicotinic and non-nicotinic receptor-mediated mechanisms responsible for anti-atrophy effects in muscle (2014)
  • Author(s): Yoshihiko Kakinuma
  • Journal Title: Receptors & Clinical Investigation Volume: 1
  • DOI: 10.14800/rci.286
  • Open Access
• [Journal Article] A non-neuronal cholinergic system regulates cellular ATP levels to maintain cell viability (2014)
  • Author(s): Oikawa S, Iketani M, Kakinuma Y
  • Journal Title: Cell Physiol Biochem Volume: 34 Issue: 3 Pages: 781-789
  • DOI: 10.1159/000363042
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Donepezil, Therapeutic Acetylcholinesterase Inhibitor, Prevents the Progression of Ventricular Dysfunction by Promoting Myocardial Glucose Utilization in Rat Model of Chronic Heart Failure Following Myocardial Infarction (2014)
  • Author(s): Mikihiko Arikawa, Yoshihiko Kakinuma, Tatsuya Noguchi, Takayuki Sato
  • Journal Title: Cardiol Pharmacol Volume: 3 Issue: 02 Pages: 1000121-1000121
  • DOI: 10.4172/2329-6607.1000121
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Antimuscle atrophy effect of nicotine targets muscle satellite cells partly through an α7 nicotinic receptor in a murine hindlimb ischemia model. (2014)
  • Author(s): Kakinuma Y, Noguchi T, Okazaki K, Oikawa S, Iketani M, Kurabayashi M, Furihata M, Sato T
  • Journal Title: Translational Research Volume: 164 Issue: 1 Pages: 32-45
  • DOI: 10.1016/j.trsl.2014.02.005
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Donepezil Can Improve Ischemic Muscle Atrophy by Activating Angiomyogenic Properties of Satellite Cells (2014)
  • Author(s): Noguchi T, Kakinuma Y, Arikawa M, Okazaki K, Hoshino E, Iiyama T, Kubo T, Kitaoka H, Doi Y, Sato T
  • Journal Title: Circulation Journal Volume: 78 Issue: 9 Pages: 2317-2324
  • DOI: 10.1253/circj.CJ-14-0095
  • NAID: 130004677615
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Anti-muscle atrophy effect of nicotine targets muscle satellite cells partly through an alpha7 nicotinic receptor in a murine hindlimb ischemia model (2014)
  • Author(s): Kakinuma Y, Tatsuya Noguchi T, Okazaki K, Oikawa S, Iketani M, Kurabayashi M, Furihata M, Sato T
  • Journal Title: Translational Research Volume: 164
  • Peer Reviewed
• [Presentation] Remote ischemic preconditioning with a specialized protocol activates the non-neuronal cardiac cholinergic system and increases ATP content in the heart (2016)
  • Author(s): 柿沼 由彦、及川詩乃、眞野 あすか
  • Organizer: 第93回日本生理学会大会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2016-03-22
• [Presentation] Chronic restraint stress triggers the dopaminergic and noradrenergic neurodegeneration-possible role of chronic stress in the onset of Parkinson's disease (2016)
  • Author(s): 洲鎌 秀永、柿沼 由彦
  • Organizer: 第93回日本生理学会大会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2016-03-22
• [Presentation] Elevation of blood pressure in F2 offspring of dams delivered from carbohydrate-restriction during pregnancy (2016)
  • Author(s): 根本 崇宏、柿沼 由彦
  • Organizer: 第93回日本生理学会大会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2016-03-22
• [Presentation] 循環器領域におけるNNA (non-neuronal ACh)の関与の可能性 (2016)
  • Author(s): 柿沼 由彦
  • Organizer: 第9回運動循環器病学研究会
  • Place of Presentation: 大田区産業プラザPio
  • Year and Date: 2016-02-20
  • Invited
• [Presentation] The fundamental significance of non-neuronal cardiac acetylcholine in terms of the pathophysiological conditions. (2014)
  • Author(s): Kakinuma Y
  • Organizer: 4th International Symposium on Non-neuronal Acetylcholine
  • Place of Presentation: Justus-Liebig-University, Main Building, Giessen, Germany
  • Year and Date: 2014-08-28 – 2014-08-30
  • Invited
• [Presentation] Another pathophysiological aspect of stress-related cardiomyopathy Glucose could be a therapeutic target for stress-induced cardiomyopathy? (2014)
  • Author(s): 柿沼由彦
  • Organizer: 第91回日本生理学会大会
  • Place of Presentation: 鹿児島大学郡元キャンパス
  • Invited
• [Presentation] たこつぼ心筋症と性差 (2013)
  • Author(s): 柿沼由彦
  • Organizer: 第66回日本自律神経学会総会
  • Place of Presentation: 愛知県産業労働センターウインクあいち
  • Invited
• [Book] 心臓の力-休めない臓器はなぜ「それ」を宿したのか (2015)
  • Author(s): 柿沼 由彦
  • Total Pages: 221
  • Publisher: 講談社（ブルーバックス）