Role of pulmonary sympathetic nerves in the regulation of the pulmonary circulation by beta-receptors on pulmonary macrophages during chronic intermittent hypoxia

• Project/Area Number: 16H05126
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General physiology
• 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): 川口 章 東海大学, 医学部, 客員教授 (30195052) ; 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) ; 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) ; 中岡 良和 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 (90393214)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000); Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 生理学 / 循環器・高血圧 / 肺高血圧 / マクロファージ / 肺交感神経 / 肺高血圧症 / 間歇的低酸素

Outline of Final Research Achievements

There are no consistent reports as to whether small animal models exposed to chronic intermittent hypoxia develop pulmonary arterial hypertension. This research revealed two sympathetic neural mechanisms that suppress the progression of pulmonary hypertension in rats exposed to six weeks of chronic intermittent hypoxia. The first is a mechanism that releases nitric oxide through activation of iNOS by β3-adrenergic receptors on macrophages recruited to the vicinity of small pulmonary arteries by intermittent hypoxia. The other involves β2-adrenergic receptors induced within the endothelium of small pulmonary arteries. These pulmonary dilatory mechanisms are activated by the accentuation of hypoxic sympathetic neural activity to inhibit the hypoxic vasoconstriction that occurs with the local mechanism in the lung. These findings suggest that pulmonary protection occurs through β-adrenergic receptors via the accentuation of hypoxic sympathetic neural activity.

Academic Significance and Societal Importance of the Research Achievements

慢性間歇的低酸素負荷ラットで見出された肺マクロファージのβ3アドレナリン受容体を介した肺高血圧症抑制機構は、肺循環の神経・免疫性調節という新たな概念を提唱し、肺高血圧症の治療・予防法開発に貢献するものと考える。
慢性間歇的低酸素は睡眠時無呼吸症候群の基本病態とされているが、この症候群の合併症である体循環の高血圧に対して、β遮断薬も治療薬の選択肢となっている。本研究で明らかになった交感神経系を介したβ受容体性肺血管拡張機構並びに肺高血圧症抑制機構は、今後の治療におけるβ遮断薬の使用に対して重大な警鐘を鳴しており、睡眠時無呼吸症候群の予後改善に大いに役立つものと期待される。

Research Products

• [Journal Article] Liraglutide Improves Renal Endothelial Function in Obese Zucker Rats on a High-Salt Diet. (2019)
  • Author(s): Sukumaran V, Tsuchimochi H, Sonobe T, Shirai M, Pearson JT
  • Journal Title: J Pharmacol Exp Ther. Volume: 363(3) Issue: 3 Pages: 375-388
  • DOI: 10.1124/jpet.118.254821
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Beta Cell-Derived Angiopoietin-1 Regulates Insulin Secretion and Glucose Homeostasis by Stabilizing Islet Microenvironment. (2019)
  • Author(s): 1.Park HS, Kim HZ, Park JS, Lee J, Lee SP, Kim H, Ahn CW, Nakaoka Y, Koh GY, Kang S.
  • Journal Title: Diabetes Volume: 68(4) Issue: 4 Pages: 774-786
  • DOI: 10.2337/db18-0864
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Regeneration-associated cells improve recovery from myocardial infarction through enhanced vasculogenesis,anti-inflammation,and cardiomyogenesis. (2019)
  • Author(s): 2.Salybekov AA, Kawaguchi AT, Masuda H, Vorateera K, Okada C, Asahara T.
  • Journal Title: PLOS ONE Volume: 13(11)
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Progressive Decrease in Coronary Vascular Function Associated With Type 2 Diabetic Heart Disease. (2018)
  • Author(s): Katare R, Pearson JT, Lew JK, Wei M, Tsuchimouchi H, Du CK, Zhan DY, Umetani K, Shirai M, Schwenke DO
  • Journal Title: Front Physiol. Volume: 9 Pages: 696-696
  • DOI: 10.3389/fphys.2018.00696
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] 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] 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] 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] Overexpression of bone morphogenetic protein-3b (BMP-3b) in adipose tissues protects against high-fat diet-induced obesity. (2017)
  • Author(s): Hino J, Nakatani M, Arai Y, Tsuchida K, Shirai M, Miyazato M, Kangawa K
  • Journal Title: Int J Obes Volume: 41 Issue: 4 Pages: 483-488
  • DOI: 10.1038/ijo.2017.15
  • Peer Reviewed / Acknowledgement Compliant
• [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
• [Journal Article] Acute arterial baroreflex-mediated changes in plasma catecholamine concentrations in a chronic rat model of myocardial infarction. (2016)
  • Author(s): Kawada T, Akiyama T, Li M, Zheng C, Turner MJ, Shirai M, Sugimachi M.
  • Journal Title: Physiol Rep. Volume: 4(15) Issue: 15
  • DOI: 10.14814/phy2.12880
  • Peer Reviewed / Open Access
• [Presentation] Liraglutide treatment improves the coronary microcirculation in Zucker obese rats on high-salt diet. (2019)
  • Author(s): Sukumaran V, Tsuchimochi H, Sonobe T, Shirai M, Pearson JT.
  • Organizer: JCS 2019
• [Presentation] Changes in the Right Coronary Microcirculation in Pulmonary Arterial Hypertension. (2019)
  • Author(s): Waddingham MT, Jin H, Sonobe , Tsuchimochi H, Asano R, Shirai M, Ogo T, Pearson JT.
  • Organizer: 9th Federation of the Asian and Oceanian Physiological Societies Congress
  • Int'l Joint Research
• [Presentation] Microangiography Reveals the Protective Role of Liraglutide on Renal Microvascular Impairment in Rats with Metabolic Syndrome. (2018)
  • Author(s): Sukumaran V, Tsuchimochi H, Tatsumi E, Shirai M, Pearson JT
  • Organizer: J Am Soc Nephrol
  • Int'l Joint Research
• [Presentation] Understanding the pathogenesis of diastolic dysfunction: from the whole heart to the level of the myofilament proteins. (2018)
  • Author(s): Waddingham MT, Tsuchimochi H, Sonobe T, Hamdani N, Yagi N, Shirai M, Pearson JT, Ogo T
  • Organizer: The 2nd JCS Council Forum on Basic CardioVascular Research.
• [Presentation] Interleukin-6/Interleukin-21 Signaling Axis in the Pathogenesis of Pulmonary Arterial Hypertension. (2018)
  • Author(s): 中岡良和2018年10月11日
  • Organizer: 第22回日本心不全学会（東京）シンポジウム6（PAH）
  • Invited
• [Presentation] Effect of insulin resistance on compound 21 mediated coronary microvascular dilation in female rats in vivo. (2017)
  • Author(s): JT Pearson, P Meagher, H Tsuchimochi, AJ Edgley, M Yoshimoto, MT Waddingham, YC Chen, KM Mirabito Colafella, LM Hilliard, K Umetani, RE Widdop, M Shirai, KM Denton
  • Organizer: ESC Congress 2017
  • 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
  • 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] 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] 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] 拡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、James T. Pearson
  • 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] 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様蛋白質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回日本生理学会総会
  • Place of Presentation: アクトシティー浜松
• [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回日本生理学会総会
  • Place of Presentation: アクトシティー浜松
• [Presentation] 拡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回日本生理学会総会
  • Place of Presentation: アクトシティー浜松
• [Presentation] Short term administration of azilsartan ameliorates diabetic cardiomyopathy in db/db mice (2017)
  • Author(s): Sukumaran Vijayakumar, Hirotsugu Tsuchimochi, Mikiyasu Shirai, James T Pearson
  • Organizer: 第９４回日本生理学会総会
  • Place of Presentation: アクトシティー浜松
• [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回日本生理学会総会
  • Place of Presentation: アクトシティー浜松