Elucidation of molecular mechanism of stress-induced cardiomyopathy through brain-heart interaction.

• Project/Area Number: 25670395
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Keio University
• Principal Investigator: FUKUDA Keiichi 慶應義塾大学, 医学部, 教授 (20199227)
• Co-Investigator(Kenkyū-buntansha): ARAI Takahide 慶應義塾大学, 医学部, 講師(非常勤) (00383894) ; KANAZAWA Hideaki 慶應義塾大学, 医学部, 特任講師 (40338033) ; SUKEGAWA Hiroaki 慶應義塾大学, 医学部, 助教 (60535607) ; TABEI Ryota 慶應義塾大学, 医学部, 助教 (20573322) ; MUNAKATA Masahito 慶應義塾大学, 医学部, 共同研究員 (40445284)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: ストレス / 脳 / サイトカイン / 脳心連関 / 炎症 / 臓器連関

Outline of Final Research Achievements

Major emotional stress may induce stress cardiomyopathy (SC), although the　precise molecular mechanisms remain unclear. Using an animal model of SC, we　first located the central cardiac sympathetic nerves (CSNs) in the hypothalamus innervating the left ventricular (LV) apex, and then investigated the gene　expression changes in these regions. We found that chemokine ligand 2 (Ccl2),　produced by activated astrocytes, strongly stimulated the central CSNs. The subsequent sympathetic activation upregulated neuropeptide Y (NPY) expression in both the stellate ganglion (SG) and CSNs. NPY in turn had a negative inotropic effect and strongly blocked -adrenergic stimulation. Thus, administration of Ccl2 into the central neurons evoked SC and increased NPY at the SG. Moreover, siRNA downregulation of NPY in the SG completely abrogated the induced SC. Overall, our results provide to explain how emotional stress affects molecular signals in the brain, leading to LV apical ballooning.

Research Products

• [Journal Article] A massive floating culture system with metabolic purification for human induced pluripotent stem cell-derived cardiomyocytes. (2014)
  • Author(s): Natsuko Hemmi, Shugo Tohyama, Kazuaki Nakajima, Hideaki Kanazawa, Tomohisa Seki, Yoshikazu Kishino, Akinori Hirano, Marina Okada, Ryota Tabei, Rei Ohno, Chihana Fujita, Fumiyuki Hattori, Shinsuke Yuasa, Motoaki Sano, Jun Fujita, and Keiichi Fukuda.
  • Journal Title: Stem Cells Translational Medicine. Volume: 3 Pages: 1473-1483
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Derivation of Transgene-free Human Induced Pluripotent Stem Cells from Human Peripheral T Cells in Defined Culture Conditions. (2014)
  • Author(s): Yoshikazu Kishino, Tomohisa Seki, Jun Fujita, Shinsuke Yuasa, Shugo Tohyama, Akira Kunitomi, Ryota Tabei, Kazuaki Nakajima, Marina Okada, Akinori Hirano, Hideaki Kanazawa, Keiichi Fukuda.
  • Journal Title: PLoS One. Volume: 9
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Distinct Metabolic Flow Enables Large-Scale Purification of Mouse and Human Pluripotent Stem Cell-Derived Cardiomyocytes. (2013)
  • Author(s): Tohyama S, Hattori F, Sano M, Hishiki T, Nagahata Y, Matsuura T, Hashimoto H, Suzuki T, Yamashita H, Satoh Y, Egashira T, Seki T, Muraoka N, Yamakawa H, Ohgino Y, Tanaka T, Yoichi M, Yuasa S, Murata M, Suematsu M, Fukuda K.
  • Journal Title: Cell Stem Cell Volume: 12 Pages: 127-137
  • Peer Reviewed
• [Journal Article] Disparity in the application of guideline-based medical therapy after percutaneous coronary intervention: analysis from the Japanese prospective multicenter registry. (2013)
  • Author(s): Endo A, Kohsaka S, Miyata H, Kawamura A, Noma S, Suzuki M, Koyama T, Ishikawa S, Momiyama Y, Nakagawa S, Sueyoshi K, Takagi S, Takahashi T, Sato Y, Ogawa S, Fukuda K.
  • Journal Title: Am J Cardiovasc Drugs. Volume: 13 Pages: 103-12
  • Peer Reviewed
• [Journal Article] Diagnostic value of portable electrocardiogram (Cardiophone) in patients complaining of palpitation. (2013)
  • Author(s): Aizawa Y, Takatsuki S, Suenaga Y, Kimura T, Nishiyama N, Fukumoto K, Tanimoto Y, Tanimoto K, Kohsaka S, Fukuda Y, Murata M, Miyoshi S, Sato T, Iwanaga S, Ogawa S, Fukuda K.
  • Journal Title: Int J Cardiol. Volume: 168(3) Pages: 2925-7
  • Peer Reviewed
• [Journal Article] Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction. (2013)
  • Author(s): Yan X, Anzai A, Katsumata Y, Matsuhashi T, Ito K, Endo J, Yamamoto T, Takeshima A, Shinmura K, Shen W, Fukuda K, Sano M.
  • Journal Title: J Mol Cell Cardiol. Volume: 62 Pages: 24-35
  • Peer Reviewed
• [Journal Article] Anatomical variations affect radial artery spasm and procedural achievement of transradial cardiac catheterization. (2013)
  • Author(s): Numasawa Y, Kawamura A, Kohsaka S, Takahashi M, Endo A, Arai T, Ohno Y, Yuasa S, Maekawa Y, Fukuda K.
  • Journal Title: Heart Vessels. Volume: 29 Pages: 49-57
  • Peer Reviewed
• [Presentation] 心臓交感神経から心臓病を診る (2014)
  • Author(s): 金澤英明、木村謙介、荒井隆秀、福田恵一
  • Organizer: 第35回日本循環制御医学会総会
  • Place of Presentation: 九州大学医学部百年講堂
  • Year and Date: 2014-07-04 – 2014-07-05
  • Invited
• [Presentation] 心不全における心臓交感神経の適応機構 (2014)
  • Author(s): 金澤英明、木村謙介、荒井隆秀、家田真樹、福田恵一
  • Organizer: 第87回日本内分泌学会学術総会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2014-04-25
  • Invited
• [Presentation] 『iPS細胞の循環器病学への臨床応用』 (2013)
  • Author(s): 福田恵一
  • Organizer: 第105回ACCP日本部会
  • Place of Presentation: 横浜
• [Presentation] 『iPS細胞の循環器領域への臨床応用』 (2013)
  • Author(s): 福田恵一
  • Organizer: 第24回心エコ-図学会特別講演
  • Place of Presentation: 東京
• [Book] 循環制御 (2014)
  • Author(s): 金澤英明、木村謙介、荒井隆秀、福田恵一
  • Publisher: 小玉株式会社出版部
• [Book] 臨床神経科学Clinical Neuroscience (2014)
  • Author(s): 金澤英明、福田恵一
  • Publisher: 中外医学社