Molecular biological approach to the pathogenesis of coronary spastic angina: A study on the role of p122 protein

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591077
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Hirosaki University
• Principal Investigator: OKUMURA Ken 弘前大学, 医学(系)研究科(研究院), 教授 (20185549)
• Co-Investigator(Kenkyū-buntansha): OSANAI Tomohiro 弘前大学, 大学院医学研究科, 准教授 (00169278)
• Project Period (FY): 2011 – 2013
• Keywords: 循環器・高血圧 / 冠攣縮 / P122蛋白 / phospholipase C / R257H亜型PLC-δ1

Research Abstract

We demonstrated that Phospholipase C(PLC)-d
1 activity in cultured skin fibroblasts from patients with coronary spastic angina(CSA) was enhanced, and found PLC-d1 864 G to A mutation in 10% of the male CSA patients. We also found p122 protein, cloned to potentiate PLC-d1 activity, and its gene expression level were enhanced in CSA. [Ca2+]i at baseline and the peak increase to acetylcholine were both higher in cells transfected with p122 than in those without p122. Further, we generated transgenic(TG) mice with the increased PLC-d1 activity specific to the VSMCs by inducing human R257H variant PLC-d1. Intravenous ergometrine induced ST segment elevation in homozygous TG. In isolated Langendorff-perfused hearts, coronary perfusion pressure was significantly increased in homozygous TG after ergometrine. Thus, the increased PLC-d1 activity causes the enhanced coronary vasomotility in TG. Both variant PLC-d1 and enhanced p122 protein were indicated to be involved in the pathogenesis of CSA.

Research Products

• [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)
  • DOI: 10.1253/circj.CJ-14-0144
  • 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: 11 Pages: 984-991
  • DOI: 10.1016/j.hrthm.2014.03.019
  • Peer Reviewed
• [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] J-RHYTHM Registry Investigators. 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
  • Journal Title: Am J Cardiol Volume: 113 Pages: 957-962
  • DOI: 10.1016/j.amjcard.2013.11.057
  • 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, YamabeH, 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 thedeterminants of the morphology (2013)
  • Author(s): Sasaki K, Sasaki S, Kimura M, Owada S, Horiuchi D, Itoh T, Ishida Y, Okumura
  • 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
  • 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 H, 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
  • 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] Matrix metalloprotein-9 activation under cell-to-cell interaction between endothelial cells and monocytes : possible role of hypoxia and tumor necrosis factor-α (2012)
  • Author(s): Yamamoto Y, Osanai T, Nishizaki F, Sukekawa T, Izumiyama K, Sagara S, Okumura K
  • Journal Title: Heart Vessels Volume: 27 Pages: 624-633
  • DOI: 10.1007/s00380-011-0214-5
  • Peer Reviewed
• [Journal Article] Br-DIF-1 accelerates dimethyl sulphoxide-induced differentiation of P19CL6 embryonic carcinoma cells into cardiomyocytes (2012)
  • Author(s): Seya K, Kanemaru K, Matsuki M, Hongo K,Kitahara H, Kikuchi H, Oshima Y, Kubohara Y, Okumura K, Motomura S, Furukawa KI
  • Journal Title: Br J Pharmacol Volume: 165 Pages: 870-879
  • DOI: 10.1111/j.1476-5381.2011.01541.x
  • Peer Reviewed
• [Journal Article] Estrogen attenuates coupling factor 6-induced salt-sensitive hypertension and cardiac systolic dysfunction in mice (2012)
  • Author(s): Izumiyama K, Osanai T, Sagara S, Yamamoto Y, Itoh T, Sukekawa T, Nishizaki F, Magota K, Okumura K
  • Journal Title: Hypertens Res Volume: 35 Pages: 539-546
  • DOI: 10.1038/hr.2011.232
  • Peer Reviewed
• [Journal Article] Thrombin stimulates synthesis of macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor by human proximal tubular epithelial cells in culture (2012)
  • Author(s): Shimaya Y, Shimada M, Shutto Y, Fujita T,Murakami R, Nakamura N, Yamabe H, Okumura K
  • Journal Title: Nephron Extra Volume: 2 Pages: 1-8
  • DOI: 10.1159/000335751
  • Peer Reviewed
• [Journal Article] Double-stranded RNA induces biphasic STAT1 phosphorylation by both type I interferon (IFN)- dependent and type I IFN-independent pathways (2012)
  • Author(s): Dempoya J, Matsumiya T, Imaizumi T, Hayakari R, Xing F, Yoshida H, Okumura K, Satoh K
  • Journal Title: J Virol Volume: 86 Pages: 12760-12769
  • DOI: 10.1128/JVI.01881-12
  • Peer Reviewed
• [Journal Article] Coupling factor 6-induced activation of ecto-F(1)F (o) complex induces insulin resistance, mild glucose intolerance and elevated blood pressure in mice (2012)
  • Author(s): Osanai T, Tanaka M, Magota K, Tomita H, Okumura K
  • Journal Title: Diabetologia Volume: 55 Pages: 520-529
  • DOI: 10.1007/s00125-011-2341-z
  • Peer Reviewed
• [Journal Article] Coronary Vasospasm Induced in Transgenic Mouse With Increased Phospholipase C-δ1 Activity (2012)
  • Author(s): Shibutani S, Osanai T, Ashitate T, Sagara S, Izumiyama K, Yamamoto Y, Hanada K, Echizen T, Tomita H, Fujita T, Miwa T, Matsubara H, Homma Y, Okumura K
  • Journal Title: Circulation Volume: 125 Pages: 1027-1036
  • DOI: 10.1161/CIRCULATIONAHA.111.064303
  • Peer Reviewed
• [Journal Article] Overexpression of coupling factor 6 attenuates exercise-induced physiological cardiac hypertrophy by inhibiting PI3K/Akt signaling in mice (2012)
  • Author(s): Sagara S, Osanai T, Itoh T, Izumiyama K, Shibutani S, Hanada K, Yokoyama H, Yamamoto Y, Yokota T, Tomita H, Magota K, Okumura K
  • Journal Title: J Hypertens Volume: 30 Pages: 778-786
  • DOI: 10.1097/HJH.0b013e3283505101
  • Peer Reviewed
• [Journal Article] Effects of pravastatin and rosuvastatin on the generation of adiponectin in the visceral adipose tissue in patients with coronary artery disease (2011)
  • Author(s): Yokoyama H, Saito S, Daitoku K, Fukuda I, Higuma T, Hanada H, Osanai T, Okumura K
  • Journal Title: Fundam Clin Pharmacol Volume: 25 Pages: 378-387
  • DOI: 10.1111/j.1472-8206.2010.00847.x
  • Peer Reviewed
• [Journal Article] Inhibition of P38 MAP Kinase Attenuates Left Ventricular Hypertrophy and Inhibits Progression of Systolic Dysfunction on Pressure-Overload Induced Pathological Cardiac Hypertrophy in Mice (2011)
  • Author(s): Hanada K, Osanai T, Sukekawa T, Ohya F, Izumiyama K, Sagara S, Ito T, Yamamoto Y, Sibutani S, Tomita H, Okumura K
  • Journal Title: Hirosaki Med J Volume: 62 Pages: 18-26
  • Peer Reviewed
• [Journal Article] Mutation Analysis ABCC9 Gene in Japanese Patients with Coronary Spastic Angina (2011)
  • Author(s): Shibutani S, Osanai T, Oya H, Sagara S, Izumiyama K, Yamamoto Y, Hanada K, Tomita H, Okumura K
  • Journal Title: Hirosaki Med J Volume: 62 Pages: 27-33
  • Peer Reviewed
• [Journal Article] Nongenomic response to aldosterone (2011)
  • Author(s): Osanai T, Yamada M, Okumura K
  • Journal Title: Hypertension Volume: 58 Pages: e3
  • DOI: 10.1161/HYPERTENSIONAHA.111.174680
  • 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 (2013)
  • Author(s): Ishida Y, Okumura K, et al.
  • Organizer: 米国心臓病学会(AHA2013)
  • Place of Presentation: アメリカ合衆国(ダラス)
  • Year and Date: 2013-11-17
• [Presentation] Altered Expression and Phosphorylation of L -type Calcium Channel in the Coronary Spastic Angina Mouse Model and the Effects of Diltiazem (2013)
  • Author(s): 石田祐司、奥村謙, 他
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2013-03-23
• [Presentation] Enhanced TRP C Channel Mediated Ca2+ Influx may be Involved in the Drug Resistant Coronary Spasm Induced by Enhanced Phospholipase C-δ1 (2013)
  • Author(s): 村上和男、奥村謙, 他
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2013-03-23
• [Presentation] Variant SUR2B Protein (R1546H) Detected in a Patient with Multivessel Coronary Artery Spasm (2013)
  • Author(s): 澁谷修司、奥村謙, 他
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2013-03-23