Effects of hyponatremia on cardiac susceptibility to ischemia/reperfusion injury

• Project/Area Number: 17K11578
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Emergency medicine
• Research Institution: Oita University
• Principal Investigator: TESHIMA YASUSHI 大分大学, 医学部, 講師 (10457608)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 酸化ストレス / カルシウム過負荷 / 心筋障害 / 虚血再灌流 / 電解質 / 低ナトリウム / 心筋虚血再灌流障害 / 活性酸素種 / 低ナトリウム血症 / 虚血再灌流障害 / 慢性心不全 / 細胞内カルシウム過負荷

Outline of Final Research Achievements

We investigated the effect of hyponatremia on the ability of the heart to recover from ischemia/reperfusion episodes. Cardiomyocytes were exposed to low sodium concentration (110, 120, or 130 mEq/L) for 72 h. Exposure of cardiomyocytes to each of the low sodium medium significantly increased both of ROS and intracellular Ca2+ levels compared with the exposure to the normal sodium medium. In vivo, 8 week-old male Sprague-Dawley rats were divided into four groups: control group (Con), furosemide group (Fur), low sodium diet group (Lsd), and both furosemide and low sodium diet group (Fur + Lsd). The hearts subjected to global ischemia exhibited considerable decrease in left ventricle developed pressure during reperfusion and the size of infarcts induced by ischemia/reperfusion significantly increased in the Fur, Lsd, and Fur + Lsd compared with those in the Con. Hyponatremia aggravates cardiac susceptibility to ischemia/reperfusion injury by Ca2+ overload and increasing in ROS levels.

Academic Significance and Societal Importance of the Research Achievements

低ナトリウム血症が心不全患者の予後を悪化させる関連性が以前より指摘されていた。今回の研究結果より低ナトリウム濃度への曝露が直接的に心筋細胞に作用し細胞内カルシウム過負荷や活性酸素種増加を介して細胞障害を惹起することを明らかにした。さらに低ナトリウム血症への曝露により虚血再灌流に対する脆弱性が亢進することも見出した。これらの研究結果は低ナトリウム血症の予防と補正が心疾患の発症と増悪の抑制に有効である可能性を強く示唆している。特に虚血性心疾患における心筋ダメージが低ナトリウムにより拡大することから再灌流療法前に介入することで有望な治療ターゲットとなりうると考える。

Research Products

• [Journal Article] Hyponatraemia aggravates cardiac susceptibility to ischaemia/reperfusion injury. (2019)
  • Author(s): Oniki T, Teshima Y, Nishio S, Ishii Y, Kira S, Abe I, Yufu K, Takahashi N.
  • Journal Title: Int J Exp Pathol. Volume: 100 Issue: 5-6 Pages: 350-358
  • DOI: 10.1111/iep.12338
  • Peer Reviewed
• [Journal Article] Interleukin-10 treatment attenuates sinus node dysfunction caused by streptozotocin-induced hyperglycaemia in mice (2018)
  • Author(s): Kondo Hidekazu、Kira Shintaro、Oniki Takahiro、Gotoh Koro、Fukui Akira、Abe Ichitaro、Ikebe Yuki、Kawano Kyoko、Saito Shotaro、Aoki Kohei、Okada Norihiro、Nagano Yasuko、Akioka Hidefumi、Shinohara Tetsuji、Akiyoshi Kumiko、Masaki Takayuki、Teshima Yasushi、Yufu Kunio、Nakagawa Mikiko、Takahashi Naohiko
  • Journal Title: Cardiovascular Research Volume: 115 Issue: 1 Pages: 57-70
  • DOI: 10.1093/cvr/cvy162
  • Peer Reviewed / Open Access
• [Journal Article] Role of atrial endothelial cells in the development of atrial fibrosis and fibrillation in response to pressure overload (2017)
  • Author(s): Kume O, Teshima Y, Abe I, Ikebe Y, Oniki T, Kondo H, Saito S, Fukui A, Yufu K, Miura M, Shimada T, Takahashi N
  • Journal Title: Cardiovasc Pathol Volume: 27 Pages: 18-25
  • Peer Reviewed
• [Journal Article] Macrophage Infiltration Into the Endothelium of Atrial Tissue in Atrial Fibrillation (2017)
  • Author(s): Sonoda Y, Teshima Y, Abe I, Ebata Y, Oniki T, Kira S, Kondo H, Saito S, Yufu K, Miyamoto S, Shimada T, Takahashi N
  • Journal Title: Circulation Journal Volume: 81 Issue: 11 Pages: 1742-1744
  • DOI: 10.1253/circj.CJ-16-1072
  • NAID: 130006179780
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Presentation] 血糖変動が洞機能に及ぼす影響 (2019)
  • Author(s): 鬼木崇裕
  • Organizer: 日本循環器学会
• [Presentation] Glucose fluctuations impair cardiac sinus node function in diabetic mice (2019)
  • Author(s): 鬼木崇裕
  • Organizer: 第3回日本循環器学会基礎研究フォーラム
• [Presentation] 低ナトリウム血症による心筋虚血耐性の低下とその機序について (2018)
  • Author(s): 鬼木崇裕、手嶋泰之、髙橋尚彦
  • Organizer: 第28回日本病態生理学会
• [Presentation] Hyponatremia Aggravates Cardiac Susceptibility to Ischemia/Reperfusion Injury (2018)
  • Author(s): Oniki T,Teshima Y,Kira S,Miyoshi M,Abe I,Ikebe Y,Yufu K,Takahashi N.
  • Organizer: 第2回日本循環器学会基礎研究フォーラム
• [Presentation] Hyponatremia Aggravates Cardiac Susceptibility to Ischemia/Reperfusion Injury (2018)
  • Author(s): Oniki T,Teshima Y,Kira S,Miyoshi M,Abe I,Ikebe Y,Yufu K,Takahashi N.
  • Organizer: 第65回日本不整脈心電学会学術大会
• [Presentation] 低ナトリウム曝露による心筋虚血耐性への影響 (2017)
  • Author(s): 鬼木崇裕
  • Organizer: 第27回日本病態生理学会大会