冠攣縮性狭心症の成因に関する分子生物学的研究：Ｐ１２２蛋白の役割の確立

2013 Fiscal Year Annual Research Report

• Project/Area Number: 23591077
• 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)
• Keywords: 循環器・高血圧 / 冠攣縮 / P122蛋白 / Phospholipase C / R257H亜型PLC-δ1

Research Abstract

【背景・目的・方法】Phospholipase C(PLC)-δ1活性を制御するp122(DLC1)蛋白に着目し、冠攣縮性狭心症(CSA)患者のp122遺伝子および蛋白発現を検討した。PLC活性を亢進させるヒトR257H亜型PLC-δ1を血管平滑筋特異的に過剰発現させたマウス(PLC-TG)を作成し、さらにP122遺伝子を過剰発現したマウス(P122-TG)でも冠攣縮誘発性を検討した。
【結果】CSA患者においてp122遺伝子発現と蛋白発現がコントロール例に比して有意に亢進していた。PLC活性との関連を見ると、大動脈平滑筋細胞にp122蛋白を過剰発現させるとPLC活性が亢進し、さらにアセチルコリン刺激に対する細胞内カルシウムイオン濃度が上昇していた。一方、PLC-TGマウスの冠動脈、大動脈ならびに腸間膜動脈のPLC活性が野生型と比べて有意に亢進しており、エルゴメトリン投与により心電図ST上昇ならびに高度房室ブロックが観察された。P122-TGにエルゴノビンを投与すると著明なST上昇と房室ブロックが観察された。
【結論】①PLC-δ1活性の機序の1つとしてp122蛋白の発現亢進が示唆された。②PLC-TGマウスは臨床例に近似したCSA動物モデルであると考えられた（Circulation2012)。③ジルチアゼムは本PLC-TGマウスにおける冠攣縮誘発阻止に有効であり、臨床例と同じフェのタイプモデルであった。④P122-TGマウスもCSA動物モデルとなることが示唆された。いずれもPLC-δ1の冠攣縮への因子を支持する所見であり冠攣縮の病態解明に大きく寄与すると考えられる。

Research Products

• [Journal Article] High correlation of estimated local conduction velocity with natural logarithm of bipolar electrogram amplitude in the reentry circuit of atrial flutter. (2014)
  • Author(s): Itoh T, Kimura M, Sasaki S, Owada S, Horiuchi D, Sasaki K, Ishida Y, Takahiko K, Okumura K.
  • Journal Title: J Cardiovasc Electrophysiol. Volume: 25 Pages: 387-394
  • DOI: 10.1111/jce.12329.
  • Peer Reviewed
• [Journal Article] Syncope in high-risk cardiomyopathy patients with implantable defibrillators: frequency, risk factors, mechanisms, and association with mortality: results from the multicenter automatic defibrillator implantation trial-reduce inappropriate therapy (MADIT-RIT) study. (2014)
  • Author(s): Ruwald MH, Okumura K, Kimura T, Aonuma K, Shoda M, Kutyifa V, Ruwald AC, McNitt S, Zareba W, Moss AJ.
  • Journal Title: Circulation. Volume: 129 Pages: 545-552
  • DOI: 10.1161/CIRCULATIONAHA.113.004196.
  • 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 K, Itoh T, Ishida Y, Kinjo T, Tomita H, Okumura K.
  • Journal Title: Heart Rhythm. Volume: in press Pages: in press
  • DOI: 10.1016/j.hrthm.2014.03.019.
  • Peer Reviewed
• [Journal Article] Impact of gender on the prognosis of patients with nonvalvular atrial fibrillation. (2014)
  • Author(s): Inoue H, Atarashi H, Okumura K, Yamashita T, Origasa H, Kumagai N, Sakurai M, Kawamura Y, Kubota I, Matsumoto K, Kaneko Y, Ogawa S, Aizawa Y, Chinushi M, Kodama I, Watanabe E, Koretsune Y, Okuyama Y, Shimizu A, Igawa O, Bando S, Fukatani M, Saikawa T, Chishaki A; J-RHYTHM Registry Investigators.
  • Journal Title: Am J Cardiol. Volume: 113 Pages: 957-962
  • DOI: 10.1016/j.amjcard.2013.11.057.
  • Peer Reviewed
• [Journal Article] Validation of CHA2DS2-VASc and HAS-BLED scores in japanese patients with nonvalvular atrial fibrillation. (2014)
  • Author(s): Okumura K, Inoue H, Atarashi H, Yamashita T, Tomita H, Origasa H, for the J-RHYTHM Registry Investigators.
  • Journal Title: Circ J Volume: in press Pages: in press
  • DOI: 10.1253/circj.CJ-14-0144
  • Peer Reviewed
• [Journal Article] Re-elevation of T-wave from day 2 to day 4 after successful percutaneous coronary intervention predicts chronic cardiac systolic dysfunction in patients with first anterior acute myocardial infarction. (2013)
  • Author(s): Nishizaki F, Tomita H, Yokoyama H, Higuma T, Abe N, Suzuki A, Endo T, Tateyama S, Ishida Y, Osanai T, Okumura K.
  • Journal Title: Heart Vessels Volume: 28 Pages: 704-713
  • DOI: 10.1007/s00380-012-0313-y.
  • Peer Reviewed
• [Journal Article] Cytosolic Ca2+-induced apoptosis in rat cardiomyocytes via mitochondrial NO-cGMP-protein kinase G pathway. (2013)
  • Author(s): Seya K, Ono K, Fujisawa S, Okumura K, Motomura S, Furukawa K.
  • Journal Title: J Pharmacol Exp Ther. Volume: 344 Pages: 77-84
  • DOI: 10.1124/jpet.112.198176
  • Peer Reviewed
• [Journal Article] A case of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)-associated glomerulonephritis and concurrent membranous nephropathy. (2013)
  • Author(s): Shimada M, Fujita T, Nakamura N, Narita I, Shimaya Y, Murakami R, Yamabe H, Osawa H, Okumura K.
  • Journal Title: BMC Nephrol. Volume: 14 Pages: 73
  • DOI: 10.1186/1471-2369-14-73.
  • Peer Reviewed
• [Journal Article] Revisit of typical counterclockwise atrial flutter wave in the ECG: electroanatomic studies on the determinants of the morphology. (2013)
  • Author(s): Sasaki K, Sasaki S, Kimura M, Owada S, Horiuchi D, Itoh T, Ishida Y, Okumura K.
  • Journal Title: Pacing Clin Electrophysiol. Volume: 36 Pages: 978-987
  • DOI: 10.1111/pace.12129.
  • Peer Reviewed
• [Journal Article] Acute myocardial infarction cases by a floating thrombus in the ascending aorta: A role of CD34-positive endothelial cells. (2013)
  • Author(s): Nishizaki F, Tomita H, Abe N, Kimura M, Higuma T, Osanai T, Yamauchi S, Daitoku K, Fukuda I, Kamata Y, Okumura K.
  • Journal Title: Journal of cardiology cases. Volume: 8 Pages: e88-e90
  • DOI: 10.1016/j.jccase.2013.04.003
  • Peer Reviewed
• [Journal Article] Validation of accuracy of three-dimensional left atrial CartoSoundTM and CT image integration: influence of respiratory phase and cardiac cycle. (2013)
  • Author(s): Kimura M, Sasaki S, Owada S, Horiuchi D, Sasaki K, Itoh T, Ishida Y, Kinjo T, Okumura K.
  • Journal Title: J Cardiovasc Electrophysiol. Volume: 24 Pages: 10002-10007
  • DOI: 10.1111/jce.12170.
  • Peer Reviewed
• [Journal Article] Clinical application of immunocytochemical detection of ALK rearrangement on cytology slides for detection or screening of lung adenocarcinoma. (2013)
  • Author(s): Tanaka H1, Tone K, Hayashi A, Morimoto T, Taima K, Tanaka Y, Nakagawa H, Takanashi S, Okumura K, Kurose A.
  • Journal Title: Lung Cancer. Volume: 80 Pages: 289-292
  • DOI: 10.1016/j.lungcan.2013.03.006.
  • Peer Reviewed
• [Journal Article] The long-term survival of a thymic carcinoma patient treated with S-1: a case report and literature review. (2013)
  • Author(s): Tanaka H, Morimoto T, Taima K, Tanaka Y, Nakamura K, Hayashi A, Kurose A, Okumura K, Takanashi S.
  • Journal Title: Onco Targets Ther. Volume: 7 Pages: 87-90
  • DOI: 10.2147/OTT.S54843. eCollection 2013.
  • Peer Reviewed
• [Presentation] Altered expression and phosphorylation levels of L-type calcium channel play a critical role in the mouse model of coronary spastic angina.
  • Author(s): Ishida Y, Okumura K.
  • Organizer: 2013年米国心臓病学会議 (AHA2013)
  • Place of Presentation: アメリカ合衆国（ダラス）