Elucidation of the transition mechanism of right ventricular hypertrophy to failure due to chronic hypoxia

• Project/Area Number: 25860184
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Environmental physiology(including physical medicine and nutritional physiology)
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Inagaki Tadakatsu 国立研究開発法人国立循環器病研究センター, 研究所, 上級研究員 (20638366)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2015: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 右心肥大 / 右心不全 / 肺高血圧症 / 冠動脈 / 低酸素 / Su5416 / 血管造影 / 血管内皮機能 / 肺高血圧 / 慢性低酸素

Outline of Final Research Achievements

Pulmonary hypertension (PH) causes cardiac hypertrophy in right ventricles (RV), and eventually leads to RV failure due to persistently elevated ventricular afterload. We hypothesized that the mechanical stress of RV associated with increased afterload impairs vasodilative function of the right coronary artery (RCA) in PH. Using microangiography, we compared the vascular function of RCA in the PH and control rats. Endothelium-dependent and -independent vasodilative responses were significantly attenuated in the middle and small arteries in the severe PH rats and the presence of abnormal constriction mechanism was revealed in the right coronary circulation of severe PH rat. The observed impaired vasodilative function of RCA in PH model suggests that impaired RCA function might have causal relationship with RV failure in the patients with severe PH.

Research Products

• [Int'l Joint Research] モナッシュ大学/モナッシュバイオイメージングセンター(オーストラリア)
• [Int'l Joint Research] オタゴ大学(ニュージーランド)
• [Journal Article] pH buffering of single rat skeletal muscle fibers in the in vivo environment. (2016)
  • Author(s): Yoshinori Tanaka, Tadakatsu Inagaki, David C. Poole and Yutaka Kano.
  • Journal Title: American Journal of Physiology - Regulatory, Integrative and Comparative Physiology. Volume: in press Issue: 10 Pages: R926-R933
  • DOI: 10.1152/ajpregu.00501.2015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Monoamine oxidase-induced hydroxyl radical production and cardiomyocyte injury during myocardial ischemia-reperfusion in rats. (2016)
  • Author(s): Inagaki T, Akiyama T, Du CK, Zhan DY, Yoshimoto M, Shirai M.
  • Journal Title: Free Radic Res. Volume: Apr 24 Pages: 1-9
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Ghrelin promotes functional angiogenesis in a mouse model of critical limb ischemia through activation of pro-angiogenic microRNAs (2016)
  • Author(s): Rajesh Katare, Shruti Rawal, Pujika E Munasinghe, Parul Dixit, Hirotsugu Tsuchimochi, Tadakatsu Inagaki, Yutaka Fujii, Keiji Umetani, Kenji Kangawa, Mikiyasu Shirai, Daryl Schwenke
  • Journal Title: Endocrinology Volume: 157 Issue: 2 Pages: 432-445
  • DOI: 10.1210/en.2015-1799
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Microvascular oxygen partial pressure during hyperbaric oxygen in diabetic rat skeletal muscle. (2015)
  • Author(s): Kohei Yamakoshi, Kazuyoshi Yagishita, Hirotsugu Tsuchimochi, Tadakatsu Inagaki, Mikiyasu Shirai,
  • Journal Title: Am. J. Physiol. Regul. Integr. Comp. Physiol Volume: 309(12) Issue: 12 Pages: 1512-1520
  • DOI: 10.1152/ajpregu.00380.2015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension (2015)
  • Author(s): Hashimoto-Kataoka T, Hosen N, Sonobe T, Arita Y, Yasui T, Masaki T, Minami M, Inagaki T, Miyagawa S, Sawa Y, Murakami M, Kumanogoh A, Yamauchi-Takihara K, Okumura M, Kishimoto T, Komuro I, Shirai M, Sakata Y, and Nakaoka Y
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: Early Edition Issue: 20 Pages: 1-10
  • DOI: 10.1073/pnas.1424774112
  • Peer Reviewed / Open Access
• [Journal Article] Chronic Rho-kinase inhibition improves left ventricular contractile dysfunction in early type-1 diabetes by increasing myosin cross-bridge extension. (2015)
  • Author(s): Waddingham MT, Edgley AJ, Astolfo A, Inagaki T, Fujii Y, Du CK, Zhan DY, Tsuchimochi H, Yagi N, Kelly DJ, Shirai M, Pearson JT.
  • Journal Title: Cardiovasc Diabetol Volume: 14 Issue: 1 Pages: 92-105
  • DOI: 10.1186/s12933-015-0256-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pulmonary Macrophages Attenuate Hypoxic Pulmonary Vasoconstriction via β3AR/iNOS Pathway in Rats Exposed to Chronic Intermittent Hypoxia (2015)
  • Author(s): Hisashi Nagai, Ichiro Kuwahira, Daryl O. Schwenke, Hirotsugu Tsuchimochi, Akina Nara, Sayoko Ogura, Takashi Sonobe, Tadakatsu Inagaki, Yutaka Fujii, Rutsuko Yamaguchi, Lisa Wingenfeld, Keiji Umetani, Tatsuo Shimosawa, Kenichi Yoshida, Koichi Uemura, James T. Pearson, Mikiyasu Shirai
  • Journal Title: PLoS ONE Volume: 10 Issue: 7 Pages: 1-20
  • DOI: 10.1371/journal.pone.0131923
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Beta2-adrenergic receptor-dependent attenuation of hypoxic pulmonary vasoconstriction prevents progression of pulmonary arterial hypertension in intermittent hypoxic rats (2014)
  • Author(s): Hisashi Nagai, Ichiro Kuwahira, Daryl O. Schwenke, Hirotsugu Tsuchimochi, Akina Nara, Tadakatsu Inagaki, Sayoko Ogura, Yutaka Fujii, Keiji Umetani, Tatsuo Shimosawa, Kenichi Yoshida, James T. Pearson, Koichi Uemura, Mikiyasu Shirai
  • Journal Title: PLOS ONE Volume: 10 Issue: 10 Pages: 1-10
  • DOI: 10.1371/journal.pone.0110693
  • Peer Reviewed / Open Access
• [Journal Article] Myocardial interstitial levels of serotonin and its major metabolite, 5-hydroxyindole acetic acid, in in vivo rat heart (2014)
  • Author(s): Cheng-Kun Du, Dong-Yun Zhan, Tsuyoshi Akiyama, Takashi Sonobe, Tadakatsu Inagaki, Mikiyasu Shirai
  • Journal Title: Life Sciences Volume: １１７ Issue: 1 Pages: 33-39
  • DOI: 10.1016/j.lfs.2014.09.019
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pulmonary vascular tone is dependent on the central modulation of sympathetic nerve activity following chronic intermittent hypoxia (2014)
  • Author(s): Mikiyasu Shirai, Hirotsugu Tsuchimochi, Hisashi Nagai, Emily Gray, James Todd Pearson, Takashi Sonobe, Misa Yoshimoto, Tadakatsu Inagaki, Yutaka Fujii, Keiji Umetani, Ichiro Kuwahira, Daryl Schwenke
  • Journal Title: Basic Research in Cardiology Volume: 109 Issue: 5 Pages: 432-432
  • DOI: 10.1007/s00395-014-0432-y
  • Peer Reviewed
• [Presentation] 肺高血圧ラットの右冠動脈では血管拡張機能が低下する：放射光微小血管造影による評価 (2016)
  • Author(s): 稲垣 薫克, 土持 裕胤, 藤井 豊, ピアソン ジェームズ, シュウェンキ ダリル, 梅谷 啓二, 白井 幹康
  • 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] 放射光微小血管造影法による肺高血圧モデルラットの冠血管機能評価 (2016)
  • Author(s): 稲垣薫克
  • Organizer: 第6回Basic and Clinical PH Conference
  • Place of Presentation: リーガロイヤルホテル大阪
  • Year and Date: 2016-02-04
  • Invited
• [Presentation] 心臓間質におけるヒドロキシルラジカル測定法の開発 (2015)
  • Author(s): 稲垣薫克、秋山剛、白井幹康
  • Organizer: 第70回日本体力医学会大会
  • Place of Presentation: 和歌山県民文化会館
  • Year and Date: 2015-09-18
• [Presentation] Role of monoamine oxidase on hydroxyl radical production during ischemia/reperfusion in anesthetized rats (2015)
  • Author(s): Tadakatsu Inagaki, Tsuyoshi Akiyama, Dong-Yun Zhan, Ceng-Kun Du, Mikiyasu Shirai
  • Organizer: 日本生理学会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] Importance of body temperature regulation for evaluation of cardiac function in anesthetised mice (2015)
  • Author(s): Hirotugu Tsuchimochi, Tadakatsu Inagaki, Mikiyasu Shirai
  • Organizer: 日本生理学会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] Aerobic tredmill training prevents the obesity caused by gene disruption of Ca2+-sensor protein mice (2015)
  • Author(s): Shigeo Wakabayashi,Shu Nakao, Tadakatsu Inagaki, Hirotsugu Tsuchimochi, Tomoe Nakamura-Nishitani, Mikiyasu Shirai
  • Organizer: 日本生理学会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] 動的運動時の心拍数調節におけるTRPV1チャネルおよびカプサイシン感受性神経の役割 (2014)
  • Author(s): 土持裕胤、稲垣薫克、白井幹康
  • Organizer: 日本体力医学会
  • Place of Presentation: 長崎
  • Year and Date: 2014-09-19 – 2014-09-21
• [Presentation] 高気圧高酸素に対する糖尿病の循環調節機構 (2014)
  • Author(s): 山越康平、柳下和慶、土持裕胤、稲垣薫克、白井幹康、狩野豊
  • Organizer: 日本体力医学会
  • Place of Presentation: 長崎
  • Year and Date: 2014-09-19 – 2014-09-21
• [Presentation] 慢性低酸素により生じる右心室肥大におけるNCS-1の働き
  • Author(s): 稲垣 薫克
  • Organizer: 第27回呼吸研究会
  • Place of Presentation: 電気通信大学（東京）
• [Remarks] 国立循環器病センター・心臓生理機能部HP
  • URL: http://www.ncvc.go.jp/res/divisions/cardiac_physiology/