冠攣縮性狭心症動物モデルを用いた冠攣縮の成因と治療に対する分子生物学的アプローチ

2014 Fiscal Year Research-status Report

• Project/Area Number: 26461120
• Research Institution: Hirosaki University
• Principal Investigator: 奥村 謙 弘前大学, 医学(系)研究科(研究院), 教授 (20185549)
• Co-Investigator(Kenkyū-buntansha): 長内 智宏 弘前大学, 医学(系)研究科(研究院), 准教授 (00169278)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 冠攣縮 / P122蛋白 / R257H亜型PLC-δ1

Outline of Annual Research Achievements

①変異型Phospholipase C（PLC）を血管平滑筋に過剰発現させたtransgenic mouse（PLC-TG）を用いて、経静脈的エルゴノビン（50mg/kg）投与により誘発された冠攣縮が、カルシウム拮抗薬（ジルチアゼム60 mg/kg/日、経口投与14日間）により抑制されるかどうかを、体表面心電図による心電図変化（心拍数やST-T変化、房室ブロック）により検討した。さらにカルシウム拮抗薬による降圧の影響を除外するため、他の降圧薬（利尿薬トリクロルメチアジド1 mg/kg/日、経口投与14日間）を用いて同様の実験を行った。その結果ジルチアゼム投与では冠攣縮が抑制されたが、トリクロルメチアジドでは抑制されなかった。またこの結果は降圧効果とは無関係であった。
②PLC活性を亢進させる物質であるp122蛋白を血管平滑筋に過剰発現させたtransgenic mouse（p122-TG）を作成し、免疫染色にてこのことを確認した。さらに頚静脈的エルゴノビン投与により体表面心電図にてST上昇が観察され、冠攣縮が誘発された。
p122TGマウスの心臓ならびに大動脈を速やかに摘出し、ランゲンドルフ灌流装置にて実験を行った。p122TGマウスではエルゴノビンを投与後の圧センサーにて冠動脈灌流圧の上昇を認め、冠攣縮が誘発されたと考えられた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

交付申請書に記載された平成２６年度の研究計画がおおむね実行され、カルシウム拮抗薬による冠攣縮抑制効果の作用機序解明に向けて、非常に興味深い結果が得られており、上記区分(2)に該当すると思われる。

Strategy for Future Research Activity

交付申請書の研究計画に沿った実験をすすめていく。特にAKAP79/150の冠攣縮における役割をAKAP79/150ノックアウトマウスを用いて検討し、AKAP79/150の細胞内カルシウムイオン上昇における役割を明らかにしていく。

Research Products

• [Journal Article] CHA2DS2-VASc and HAS-BLED scores and activated partial thromboplastin time for prediction of high plasma concentration of dabigatran at trough. (2015)
  • Author(s): Owada S, Tomita H, Kinjo T, Ishida Y, Itoh T, Sasaki K, Horiuchi D, Kimura M, Sasaki S, Okumura K.
  • Journal Title: Thorombosis Res. Volume: 135 Pages: 62-67
  • DOI: 10.1016/j.thromres.2014.10.025.
  • Peer Reviewed
• [Journal Article] Plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 as a novel prognostic biomarker in patients with ST-segment elevation acute myocardial infarction. (2015)
  • Author(s): Higuma T, Abe N, Tateyama S, Endo T, Shibutani S, Yokoyama H, Hanada K, Yamada M, Tomita H, Hanada H, Osanai T, Kume N, Okumura K.
  • Journal Title: Circ J. Volume: 79 Pages: 641-648
  • DOI: 10.1253/circj.CJ-14-0904.
  • Peer Reviewed
• [Journal Article] Deeply re-inverted T-wave at 14 days after the onset of first anterior acute myocardial infarction predicts improved left ventricular function at 6 months. (2015)
  • Author(s): Yokoyama H, Tomita H, Nishizaki F, Hanada K, Shibutani S, Yamada M, Abe N, Higuma T, Osanai T, Okumura K.
  • Journal Title: Clin Cardiol. Volume: 38 Pages: 157-163
  • DOI: 10.1002/clc.22366.
  • Peer Reviewed
• [Journal Article] Comparison of lesion formation between contact force-guided and non-guided circumferential pulmonary vein isolation: A prospective, randomized study. (2014)
  • Author(s): Kimura M, Sasaki S, Owada S, Horiuchi D, Sasaki S, Itoh T, Ishida Y, Kinjo T, Tomita H, Okumura K.
  • Journal Title: Heart Rhythm Volume: 11 Pages: 984-991
  • DOI: 10.1016/j.hrthm.2014.03.019.
  • Peer Reviewed
• [Journal Article] 8-Methyltryptanthrin-Induced Differentiation of P19CL6 Embryonal Carcinoma Cells into Spontaneously Beating Cardiomyocyte-like Cells. (2014)
  • Author(s): Seya K, Yamaya A, Kamachi S, Murakami M, Kitahara H, Kawakami J, Okumura K, Murakami M, Motomura S, Furukawa K.
  • Journal Title: J Nat Prod. Volume: 77 Pages: 1413-1419
  • DOI: 10.1021/np500108r.
  • Peer Reviewed
• [Journal Article] Coupling factor 6 attenuates CXCR4 expression through the HIF-1α and c-Src pathways and promotes endothelial apoptosis and inflammation. (2014)
  • Author(s): Suzuki A, Osanai T, Tanaka M, Tomita H, Magota K, Okumura K.
  • Journal Title: Hypertens Res. Volume: 37 Pages: 708-715
  • DOI: 10.1038/hr.2014.65.
  • Peer Reviewed
• [Journal Article] Usefulness of the wearable cardioverter-defibrillator in patients at high risk for sudden cardiac death. (2014)
  • Author(s): Sasaki S, Tomita H, Shibutani S, Izumiyama K, Higuma T, Itoh T, Sasaki S, Horiuchi D, Kimura M, Okumura K.
  • Journal Title: Circ J Volume: 78 Pages: 2987-2989
  • DOI: http://doi.org/10.1253/circj.CJ-14-1098
  • Peer Reviewed
• [Journal Article] Prognostic impact of atrial fibrillation in patients with acute myocardial infarction. (2014)
  • Author(s): Tateyama S, Higuma T, Endo T, Shibutani S, Hanada K, Yokoyama H, Yamada M, Abe N, Sasaki S, Kimura M, Okumura K.
  • Journal Title: Journal of Arrhythmia Volume: 30 Pages: 460-465
  • DOI: http://dx.doi.org/10.1016/j.joa.2013.12.006
  • Peer Reviewed
• [Presentation] Chronic Nuclear Acidosis Defines Aging and Lifespan by Histone 4 Lysine 5 Acetylation in Mice (2014)
  • Author(s): Osanai T, Okumura K.
  • Organizer: AHA2014
  • Place of Presentation: McCormick Place, Chicago, Illinois
  • Year and Date: 2014-11-19 – 2014-11-19
• [Presentation] Plaque Erosion, Compared to Plaque Rupture, is Associated With Better Outcomes After Primary Percutaneous Coronary Intervention in Patients With STsegment Elevation Myocardial Infarction. (2014)
  • Author(s): Higumt T, Okumura K.
  • Organizer: AHA2014
  • Place of Presentation: McCormick Place, Chicago, Illinois
  • Year and Date: 2014-11-19 – 2014-11-19
• [Presentation] Enhanced Trpc Channel-Mediated Ca2+ Influx in the Cells With Phospholipase C-δ1 Overexpression (2014)
  • Author(s): Murakami K, Okumura K.
  • Organizer: AHA2014
  • Place of Presentation: McCormick Place, Chicago, Illinois
  • Year and Date: 2014-11-16 – 2014-11-16
• [Presentation] Coronary Vasospasm Induced in Transgenic Mouse With Vascular Smooth Muscle- Specific Overexpression of p122RhoGAP/ DLC1. (2014)
  • Author(s): Kinjo T, Okumura K.
  • Organizer: AHA2014
  • Place of Presentation: McCormick Place, Chicago, Illinois
  • Year and Date: 2014-11-16 – 2014-11-16
• [Presentation] Incidence and Morphologic Characteristics of Plaque Erosion in Patients With Acute Myocardial Infarction: A Combined Optical Coherence Tomography and Intravascular Ultrasound Study. (2014)
  • Author(s): Takumi Higuma, et al.
  • Organizer: AHA2014
  • Place of Presentation: McCormick Place, Chicago, Illinois
  • Year and Date: 2014-11-16 – 2014-11-16