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

• Project/Area Number: 26461120
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Hirosaki University
• Principal Investigator: Okumura Ken 弘前大学, 医学研究科, 客員研究員 (20185549)
• Co-Investigator(Kenkyū-buntansha): 長内 智宏 弘前大学, 保健学研究科, 教授 (00169278)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 循環器・高血圧 / 冠攣縮 / phospholipase C / Phospholipase C / P122蛋白 / R257H亜型PLC-δ1

Outline of Final Research Achievements

We recently generated transgenic mice with enhanced phospholipase C-delta 1 activity (PLC-TG) and reported enhanced coronary vasomotility such as that seen in patients with coronary spastic angina. In the present study, we showed the efficacy of calcium antagonist for coronary spasm and its mechanism using the PLC-TG mice. Alterations in activity of calcium channels were suggested to be implicated in the therapeutic effect of calcium antagonist. Furthermore, we first clarified roles of A-kinase anchoring proteins in the coronary spasm. The present study may help better understand mechanism of the coronary spasm and contribute to the development of novel treatment strategy for drug-resistant coronary spasm.

Research Products

• [Journal Article] Enhanced transient receptor potential channel-mediated Ca2+ influx in the cells with phospholipase C-δ1 overexpression: its possible role in coronary artery spasm. (2017)
  • Author(s): Murakami K, Osanai T, Tanaka M, Nishizaki K, Kinjo T, Tanno T, Ishida Y, Suzuki A, Endo T, Tomita H, Okumura K.
  • Journal Title: Fundam Clin Pharmacol. Volume: 印刷中 Issue: 4 Pages: 383-391
  • DOI: 10.1111/fcp.12269
  • Peer Reviewed
• [Journal Article] Olmesartan Inhibits Cardiac Hypertrophy in Mice Overexpressing Renin Independently of Blood Pressure: Its Beneficial Effects on ACE2/Ang(1-7)/Mas Axis and NADPH Oxidase Expression. (2016)
  • Author(s): Tanno T, Tomita H, Narita I, Kinjo T, Nishizaki K, Ichikawa H, Kimura Y, Tanaka M, Osanai T, Okumura K.
  • Journal Title: J Cardiovasc Pharmacol. Volume: 67 Issue: 6 Pages: 503-509
  • DOI: 10.1097/fjc.0000000000000374
  • Peer Reviewed
• [Journal Article] NF-κB-dependent increase in tissue factor expression is responsible for hypoxic podocyte injury. (2016)
  • Author(s): Narita I, Shimada M, Yamabe H, Kinjo T, Tanno T, Nishizaki K, Kawai M, Nakamura M, Murakami R, Nakamura N, Tomita H, Saleem MA, Mathieson PW, Okumura K.
  • Journal Title: Clin Exp Nephrol. Volume: 20 Issue: 5 Pages: 679-688
  • DOI: 10.1007/s10157-015-1214-z
  • Peer Reviewed
• [Journal Article] Mitochondrial Inhibitory Factor Protein 1 Functions as an Endogenous Inhibitor for Coupling Factor 6. (2016)
  • Author(s): Kawai M, Osanai T, Tanaka M, Magota K, Tomita H, Okumura K.
  • Journal Title: J Cell Biochem. Volume: 117 Issue: 7 Pages: 1680-1687
  • DOI: 10.1002/jcb.25461
  • Peer Reviewed
• [Journal Article] Reduced residual conduction gaps and favourable outcome in contact force-guided circumferential pulmonary vein isolation. (2016)
  • Author(s): Itoh T, Kimura M, Tomita H, Sasaki S, Owada S, Horiuchi D, Sasaki K, Ishida Y, Kinjo T, Okumura K.
  • Journal Title: Europace. Volume: 18 Issue: 4 Pages: 531-537
  • DOI: 10.1093/europace/euv206
  • Peer Reviewed
• [Journal Article] Modified sympatheticsympathetic nerve regulation in AKAP5-null mice. (2016)
  • Author(s): Han C, Tomita H, Ohba T, Nishizaki K, Ogata Y, Matsuzaki Y, Sawamura D, Yanagisawa T, Osanai T, Imaizumi T, Matsubara A, Adachi T, Ono K, Okumura K, Murakami M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 469（4） Issue: 4 Pages: 897-902
  • DOI: 10.1016/j.bbrc.2015.12.057
  • Peer Reviewed / Open Access
• [Journal Article] Catheter ablation of ventricular arrhythmias arising from the basal septum of the right ventricle: characteristics and significance of junctional rhythm appearing during ablation. (2016)
  • Author(s): Sasaki K, Sasaki S, Kimura M, Horiuchi D, Itoh T, Ishida Y, Kinjo T, Tomita H, Okumura K.
  • Journal Title: J Interv Card Electrophysiol Volume: 45 Issue: 2 Pages: 159-167
  • DOI: 10.1007/s10840-015-0095-0
  • Peer Reviewed
• [Journal Article] Enhanced p122RhoGAP/DLC-1 expression can be a cause of coronary spasm. (2015)
  • Author(s): Kinjo T, Tanaka M, Osanai T, Shibutani S, Narita I, Tanno T, Nishizaki K, Ichikawa H, Kimura Y, Ishida Y, Yokota T, Shimada M, Homma Y, Tomita H, Okumura K.
  • Journal Title: PLOS ONE Volume: 10(12) Issue: 12 Pages: e0143884-e0143884
  • DOI: 10.1371/journal.pone.0143884
  • Peer Reviewed / Open Access
• [Journal Article] Severity and Functional Outcome of Patients with Cardioembolic Stroke Occurring during Non-vitamin K Antagonist Oral Anticoagulant Treatment. (2015)
  • Author(s): Tomita H, Hagii J, Metoki N, Saito S, Shiroto H, Hitomi H, Kamada T, Seino S, Takahashi K, Sasaki S, Yasujima M, Okumura K.
  • Journal Title: J Stroke Cerebrovasc Dis Volume: 24 Pages: 1430-7
  • Peer Reviewed
• [Journal Article] Validation of Risk Scoring System Excluding Female Sex From CHA₂DS₂-VASc in Japanese Patients With Nonvalvular Atrial Fibrillation – Subanalysis of the J-RHYTHM Registry – (2015)
  • Author(s): Tomita H, Okumura K, Inoue H, Atarashi H, Yamashita T, Origasa H, Tsushima E, on behalf of the J-RHYTHM Registry Investigators.
  • Journal Title: Circulation Journal Volume: 79 Issue: 8 Pages: 1719-1726
  • DOI: 10.1253/circj.CJ-15-0095
  • NAID: 130005089373
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [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 Issue: 1 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: Circulation Journal Volume: 79 Issue: 3 Pages: 641-648
  • DOI: 10.1253/circj.CJ-14-0904
  • NAID: 130004927094
  • ISSN: 1346-9843, 1347-4820
  • 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 Issue: 3 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 K, Itoh T, Ishida Y, Kinjo T, Tomita H, Okumura K.
  • Journal Title: Heart Rhythm. Volume: in press Issue: 6 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: 8-Methyltryptanthrin-induced differentiation of P19CL6 embryonal carcinoma cells into spontaneously beating cardiomyocyte-like cells. Volume: 77 Issue: 6 Pages: 1413-9
  • DOI: 10.1021/np500108r
  • Peer Reviewed / Acknowledgement Compliant
• [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 Issue: 8 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: Circulation Journal Volume: 78 Issue: 12 Pages: 2987-2989
  • DOI: 10.1253/circj.CJ-14-1098
  • NAID: 130004704003
  • ISSN: 1346-9843, 1347-4820
  • 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 Issue: 6 Pages: 460-465
  • DOI: 10.1016/j.joa.2013.12.006
  • Peer Reviewed
• [Presentation] Possible Involvement of Epidermal Growth Factor Receptor Transactivation in Acetylcholine Muscarinic M3 Receptor Signaling in Coronary Spasm (2017)
  • Author(s): Senoo M, Hanada K, Okumura K, et al.
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢市教育プラザ（石川県・金沢市）
• [Presentation] Trend of Anticoagulation Therapy in Patients with Non-valvular Atrial Fibrillation in a Japanese Local Region: Analysis Using the “Kokuho Database” (2017)
  • Author(s): 成田 憲紀、富田 泰史、奥村 謙
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: ANA クラウンプラザホテル金沢（石川県・金沢市）
• [Presentation] p122RhoGAP/DLC-1 Overexpression Enhances Intracellular Calcium Concentration in Response to Acetylcholine in Isolated Vascular Smooth Muscle Cells (2017)
  • Author(s): Kimura Y, Tomita H, Okumura K,et al.
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢フォーラス（石川県・金沢市）
• [Presentation] Disruption of A-kinase Anchoring Protein 150 Induces Coronary Spasm through Enhancement of Calcium Sensitization: A Potential Role of microRNA-30b (2017)
  • Author(s): Nishizaki K, Tomita H, Okumura K, et al.
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢フォーラス（石川県・金沢市）
• [Presentation] Disruption of A-kinase Anchoring Protein 150 Causes Coronary Spasm Through Enhanced Calcium Sensitization: A Potential Role of Microrna-30b (2016)
  • Author(s): Nishizaki K, Tomita H, Okumura K, et al.
  • Organizer: AHA2016
  • Place of Presentation: New Orleans, LA
  • Year and Date: 2016-11-11
• [Presentation] Enhanced p122RhoGAP/DLC-1 Expression can be a Cause of Coronary Spasm (2016)
  • Author(s): 金城貴彦、田中真実、長内智宏、澁谷修司、石田祐司、丹野倫宏、西崎公貴、市川博章、木村嘉宏、富田泰史、奥村謙
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター（宮城県、仙台市）
  • Year and Date: 2016-03-20
• [Presentation] Disruption of A-kinase Anchoring Protein 150 Induces Coronary Spasm through Enhancement of Calcium Sensitization (2016)
  • Author(s): 西崎公貴、富田泰史、市川博章、木村嘉宏、金城貴彦、丹野倫宏、田中真実、長内智宏、奥村謙
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター（宮城県、仙台市）
  • Year and Date: 2016-03-20
• [Presentation] Coronary Vasospasm Induced in Transgenic Mouse With Overexpression of p122RhoGAP/DLC1 (2015)
  • Author(s): Takahiko Kinjo, Makoto Tanaka, Tomohiro Osanai, Ikuyo Narita, Tomohiro Tannno, Kimitaka Nishizaki, Shuji Shibutani, Yuji Ishida, Hirofumi Tomita, Yoshimi Homma, and Ken Okumura
  • Organizer: AHA2015
  • Place of Presentation: オーランド市（アメリカ合衆国）
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [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
• [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
• [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
• [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
• [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