Synchrotron radiation investigation of cardiac contractile protein dynamics at end diastole in a type 2 prediabetes model rat

• Project/Area Number: 16K15452
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: SHIRAI Mikiyasu 国立研究開発法人国立循環器病研究センター, 研究所, 特任研究員 (70162758)
• Co-Investigator(Kenkyū-buntansha): 土持 裕胤 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (60379948) ; Pearson James 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (30261390)
• Co-Investigator(Renkei-kenkyūsha): TO Seikon 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 (90590646) ; KIN Mika 国立研究開発法人国立循環器病研究センター, 研究所, 研究員 (40746773) ; SEN Toun 国立研究開発法人国立循環器病研究センター, 研究所, 派遣研究員 (30616941) ; 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)
• Research Collaborator: YAGI Naoto
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 循環器・高血圧 / 糖尿病 / 心臓拡張機能障害 / 心筋収縮タンパク質 / 放射光X線回折法 / 心筋拡張機能障害 / 放射光Ｘ線回折法

Outline of Final Research Achievements

Applying our synchrotron radiation X-ray diffraction approach to the beating heart of the type 2 prediabetes Goto-Kakizaki (GK) rat, we found abnormal cardiac contractile protein dynamics in the subendocardium was associated with left ventricular diastolic dysfunction. GK rat hearts did not show altered phosphorylation state of the small myofilament proteins, but showed hypophosphorylation of titin. Myocardial soluble guanylate cyclase (sGC) protein expression and PKG activity were significantly depressed, and hypophosphorylation of titin correlated with depressed sGC-PKG activation. Synchrotron radiation microangiography enabled us to visualize the coronary circulation, which suggested that the GK rat does not have coronary endothelial dysfunction at this age, and therefore the previously hypothesised role of depressed endothelium dependent nitric oxide signaling driving diastolic dysfunction is not supported.

Research Products

• [Journal Article] Widespread Coronary Dysfunction in the Absence of HDL Receptor SR-B1 in an Ischemic Cardiomyopathy Mouse Model. (2017)
  • Author(s): Pearson JT, Yoshimoto M, Chen YC, Sultani R, Edgley AJ, Nakaoka H, Nishida M, Umetani K, Waddingham MT, Jin HL, Zhang Y, Kelly DJ, Schwenke DO, Inagaki T, Tsuchimochi H, Komuro I, Yamashita S, Shirai M.
  • Journal Title: Sci Rep Volume: Dec 22;7(1) Issue: 1 Pages: 18108-18108
  • DOI: 10.1038/s41598-017-18485-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Influence of coronary architecture on the variability in myocardial infarction induced by coronary ligation in rats. (2017)
  • Author(s): Kainuma S, Miyagawa S, Fukushima S, Tsuchimochi H, Sonobe T, Fujii Y, Pearson JT, Saito A, Harada A, Toda K, Shirai M, Sawa Y.
  • Journal Title: PLoS One Volume: 12(8) Issue: 8 Pages: e0183323-e0183323
  • DOI: 10.1371/journal.pone.0183323
  • Peer Reviewed / Open Access
• [Journal Article] Cardiac vagal control in a knock-in mouse model of dilated cardiomyopathy with a troponin mutation. (2017)
  • Author(s): Zhan DY, Du CK, Akiyama T, Morimoto S, Shimizu S, Kawada T, Shirai M, Pearson JT.
  • Journal Title: Auton Neurosci. Volume: 205 Pages: 33-40
  • DOI: 10.1016/j.autneu.2017.03.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Analysis of the microvascular morphology and hemodynamics of breast cancer in mice using SPring-8 synchrotron radiation microangiography. (2017)
  • Author(s): Torii M, Fukui T, Inoue M, Kanao S, Umetani K, Shirai M, Inagaki T, Tsuchimochi H, Pearson JT, Toi M.
  • Journal Title: J Synchrotron Radiat Volume: 24 Issue: 5 Pages: 1039-1047
  • DOI: 10.1107/s1600577517008372
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Azilsartan ameliorates diabetic cardiomyopathy in young db/db mice through the modulation of ACE-2/ANG 1-7/Mas receptor cascade. (2017)
  • Author(s): Sukumaran V, Tsuchimochi H, Tatsumi E, Shirai M, Pearson JT.
  • Journal Title: Biochem Pharmacol Volume: 144 Pages: 90-99
  • DOI: 10.1016/j.bcp.2017.07.022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of Hydroxyethyl Starch Priming on the Systemic Inflammatory Response and Lung Edema after Cardiopulmonary Bypass in a Rat Model. (2017)
  • Author(s): Fujii Y, Tanabe T, Yamashiro T, Shirai M, Takewa Y, Tatsumi E.
  • Journal Title: ASAIO J Volume: 63(5) Issue: 5 Pages: 618-623
  • DOI: 10.1097/mat.0000000000000543
  • Peer Reviewed
• [Journal Article] Myocardial interstitial levels of serotonin and its major metabolite 5-hydroxyindole acetic acid during ischemia-reperfusion. (2017)
  • Author(s): Du CK, Zhan DY, Akiyama T, Inagaki T, Shishido T, Shirai M, Pearson JT.
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: 312(1) Issue: 1 Pages: H60-H67
  • DOI: 10.1152/ajpheart.00471.2016
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Vagal denervation inhibits the increase in pulmonary blood flow during partial lung aeration at birth. (2017)
  • Author(s): Lang JA, Pearson JT, Binder-Heschl C, Wallace MJ, Siew ML, Kitchen MJ, Te Pas AB, Lewis RA, Polglase GR, Shirai M, Hooper SB.
  • Journal Title: J Physiol. Volume: 595(5) Issue: 5 Pages: 1593-1606
  • DOI: 10.1113/jp273682
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chronic intermittent hypoxia accelerates coronary microcirculatory dysfunction in insulin-resistant Goto-Kakizaki rats. (2016)
  • Author(s): Chen YC, Inagaki T, Fujii Y, Schwenke DO, Tsuchimochi H, Edgley AJ, Umetani K, Zhang Y, Kelly DJ, Yoshimoto M, Nagai H, Evans RG, Kuwahira I, Shirai M, Pearson JT.
  • Journal Title: Am J Physiol Regul Integr Comp Physiol. Volume: 311(2) Issue: 2 Pages: 426-439
  • DOI: 10.1152/ajpregu.00112.2016
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] SPring-8 synchrotron radiation imaging for analyzing cardiovascular function in anesthetized small animals (2016)
  • Author(s): Shirai M, Yagi N, Umetani K.
  • Journal Title: Folia Pharmacologica Japonica Volume: 148 Issue: 2 Pages: 92-99
  • DOI: 10.1254/fpj.148.92
  • NAID: 130005253974
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed
• [Presentation] ローキナーゼ及び酸化ストレスによる心筋サルコメア機能の調節作用 (2017)
  • Author(s): JT Pearson, H Tsuchimochi, N Yagi, M Shirai
  • Organizer: 第94回日本生理学会大会（浜松）
• [Presentation] Investigating in vivo myocardial and coronary molecular pathophysiology in mice with X-ray radiation imaging approaches (2017)
  • Author(s): JT Pearson, M Shirai
  • Organizer: 第12回上原国際シンポジウム2017 Make Life Visible
  • Int'l Joint Research
• [Presentation] Beta-blockade prevents coronary microvascular endothelial dysfunction in non-obese salt-sensitive insulin resistant rats on a high salt diet (2017)
  • Author(s): H Tsuchimochi, H Thambyah, AJ Edgley, T Inagaki, MT Waddingham, YC Chen, CK Du, DY Zhan, V Sukumaran, T Sonobe, K Umetani, M Shirai, JT Pearson
  • Organizer: ESC Congress 2017（Barcelona)
  • Int'l Joint Research
• [Presentation] Bolus ghrelin administration ameliorates the inflammatory response and oxidative stress during percutaneous cardiopulmonary support in a rat model. (2017)
  • Author(s): Sukumaran V, Tsuchimochi H, Tatsumi E, Shirai M and Pearson JT.
  • Organizer: Experimental Biology meeting 2017
  • Int'l Joint Research
• [Presentation] Liraglutide treatment improves renal vascular function in Zucker rats as visualized by microangiography. (2017)
  • Author(s): Sukumaran V, Tsuchimochi H, Tatsumi E, Shirai M and Pearson JT.
  • Organizer: American Society of Nephrology meeting Kidney Week 2017
  • Int'l Joint Research
• [Presentation] 拡張型心筋症ノックインマウスにおける心臓交感神経終末ノルエピネフリン動態異常 (2017)
  • Author(s): 戦 冬雲、杜 成坤、秋山 剛、森本 幸生、白井 幹康、James T. Pearson
  • Organizer: 第94回日本生理学会大会（浜松）
• [Presentation] ローキナーゼ及び酸化ストレスによる心筋サルコメア機能の調節作用 (2017)
  • Author(s): ピアソン ジェームズ、土持裕胤、八木直人、白井幹康
  • Organizer: 第94回日本生理学会大会
  • Place of Presentation: アクトシティ浜松
• [Presentation] 低酸素により誘発される心肥大におけるカルシニュリンB用蛋白質3（CHP3)の新しい役割 (2017)
  • Author(s): 金美花、若林繁夫、古林創史、土持裕胤、白井幹康、ピアソン ジェームズ、大郷剛
  • Organizer: 第94回日本生理学会大会
  • Place of Presentation: アクトシティ浜松
• [Presentation] 拡張型心筋症ノックインマウスにおける心臓ノルエピネフリン動態異常 (2017)
  • Author(s): 戦冬雲、杜成坤、秋山剛、森本幸生、白井幹康、ピアソン ジェームズ
  • Organizer: 第94回日本生理学会大会
  • Place of Presentation: アクトシティ浜松
• [Presentation] 張型心筋症ノックインマウスに対するドネペジルの治療効果 (2017)
  • Author(s): 杜成坤、戦冬雲、森本幸生、秋山剛、白井幹康、ピアソン ジェームズ
  • Organizer: 第94回日本生理学会大会
  • Place of Presentation: アクトシティ浜松
• [Presentation] Short term administration of azilsartan ameliorates diabetic cardiomyopathy in db/db mice. (2017)
  • Author(s): Sukumaran Vijayakumar, Hirotsugu Tsuchimochi, Mikiyasu Shirai, James Pearson
  • Organizer: 第94回日本生理学会大会
  • Place of Presentation: アクトシティ浜松