Elucidation of novel mechanism and development of treatment strategy for coronary spastic angina through regulation of calcium sensitization

• Project/Area Number: 16K09489
• 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: Tomita Hirofumi 弘前大学, 医学研究科, 教授 (00431437)
• Co-Investigator(Kenkyū-buntansha): 奥村 謙 弘前大学, 医学研究科, 客員研究員 (20185549)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: 冠攣縮 / カルシウム / カルベジロール / 冠攣縮性狭心症 / カルシウム感受性

Outline of Final Research Achievements

In the present study, we first showed that coronary spasm was induced in A-kinase anchoring protein knockout mice with enhanced calcium sensitization, which was supported by increased expression of calcium/calmodulin-dependent protein kinase II. Furthermore, we clarified inhibitory effects of carvedilol on coronary spasm in this mouse model. The present study may help better understand mechanism of the coronary spasm and contribute to the development of novel treatment strategy for coronary spastic angina.

Academic Significance and Societal Importance of the Research Achievements

これまでカルベジロールの冠攣縮に対する効果は全く検討されておらず、本研究の成果は新しい作用機序に基づく新たな冠攣縮性狭心症治療の開発に寄与する可能性がある。臨床的にもカルシウム拮抗薬抵抗性の難治性冠攣縮性狭心症患者は少なくなく、その機序解明ならびに治療法の開発への応用が期待される。さらに冠攣縮は異型狭心症のみでなく、一部の労作狭心症や急性心筋梗塞症、突然死の病態にも関与する。本研究はこれらの疾患に対する新しい治療法の開発という点においても十分に意義深い。

Research Products

• [Journal Article] Rivaroxaban, a Direct Factor Xa Inhibitor, Ameliorates Hypertensive Renal Damage Through Inhibition of the Inflammatory Response Mediated by Protease-Activated Receptor Pathway (2019)
  • Author(s): Ichikawa H, Shimada M, Narita M, Narita I, Kimura Y, Tanaka M, Osanai T, Okumura K, Tomita H.
  • Journal Title: Journal of the American Heart Association Volume: 8 Issue: 8
  • DOI: 10.1161/jaha.119.012195
  • Peer Reviewed / Open Access
• [Journal Article] Safety and Efficacy of Subcutaneous Cardioverter Defibrillator in Patients at High Risk of Sudden Cardiac Death ― Primary Japanese Experience ― (2018)
  • Author(s): Sasaki S, Tomita H, Tsurugi T, Ishida Y, Shoji Y, Nishizaki K, Kinjo T, Endo T, Nishizaki F,Hanada K, Sasaki K, Horiuchi D, Kimura M, Higuma T, Okamatsu H, Tanaka Y, Koyama J, Okumura K.
  • Journal Title: Circulation Journal Volume: 82 Issue: 6 Pages: 1546-1551
  • DOI: 10.1253/circj.CJ-17-1001
  • NAID: 130006744337
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2018-05-25
  • Peer Reviewed / Open Access
• [Journal Article] Novel anti-aging gene NM_026333 contributes to proton-induced aging via NCX1-pathway (2018)
  • Author(s): Osanai T, Tanaka M, Mikami K, Kitajima M, Tomisawa T, Magota K, Tomita H, Okumura K.
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 125 Pages: 174-184
  • DOI: 10.1016/j.yjmcc.2018.10.021
  • Peer Reviewed
• [Journal Article] Covert atrial fibrillation and atrial high-rate episodes as a potential cause of embolic strokes of undetermined source: their detection and possible management strategy. (2018)
  • Author(s): Tomita H, Sasaki S, Hagii J, Metoki N.
  • Journal Title: J Cardiol Volume: 印刷中 Issue: 1 Pages: 1-9
  • DOI: 10.1016/j.jjcc.2018.03.002
  • Peer Reviewed
• [Journal Article] The relationship of serum eicosapentaenoic acid levels with J-waves in a general population: Analysis of the Iwaki Health Promotion Project. (2018)
  • Author(s): Kimura Y, Yamada, M, Hanada K, Endo T, Narita N, Narita M, Senoo M, Yonekura M, Ichikawa H, Kurauchi S, Nakaji S, Okumura K, Tomita H.
  • Journal Title: Int Heart J Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial inhibitory factor protein 1 attenuates coupling factor 6-induced?aging signal (2018)
  • Author(s): Osanai Tomohiro、Tanaka Makoto、Mikami Kasumi、Kitajima Maiko、Magota Koji、Tomita Hirofumi、Okumura Ken
  • Journal Title: Journal of Cellular Biochemistry Volume: 印刷中 Issue: 7 Pages: 6194-6203
  • DOI: 10.1002/jcb.26828
• [Journal Article] Medaka as a model for ECG analysis and the effect of verapamil. (2018)
  • Author(s): Yonekura M, Kondoh N, Han C, Toyama Y, Ohba T,Ono K, Itagaki S, Tomita H, Murakami M.
  • Journal Title: J Pharmacol Sci Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Blood pressure-independent effect of olmesartan on albuminuria in mice overexpressing renin: Its beneficial role in the ACE2/Ang (1-7)/Mas axis and NADPH oxidase expression. (2018)
  • Author(s): Ichikawa H, Narita I, Narita M, Tanno T, Yokono Y, Kimura Y, Tanaka M, Osanai T, Okumura K, Tomita H
  • Journal Title: Int Heart J Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Impact of Atrial Natriuretic Peptide Value for Predicting Paroxysmal Atrial Fibrillation in Ischemic Stroke Patients. (2017)
  • Author(s): Shiroto H, Tomita H, Hagii J, Metoki N, Fujita A, Kamada T, Takahashi K, Saito S, Sasaki S, Hitomi H, Seino S, Baba Y, Uchizawa T, Iwata M, Matsumoto S, Yasujima M, Okumura K.
  • Journal Title: J Stroke Cerebrovasc Dis Volume: 26 Issue: 4 Pages: 772-778
  • DOI: 10.1016/j.jstrokecerebrovasdis.2016.10.016
  • Peer Reviewed
• [Journal Article] Safety and efficacy of contemporary catheter ablation for atrial fibrillation patients with a history of cardioembolic stroke in the era of direct oral anticoagulants. (2017)
  • Author(s): Nishizaki K, Itoh T, Kimura M, Tsushima Y, Shoji Y, Kinjo T, Ishida Y, Sasaki K, Horiuchi D, Sasaki S, Tomita H, Okumura K.
  • Journal Title: J Cardiol Volume: 70 Issue: 1 Pages: 86-91
  • DOI: 10.1016/j.jjcc.2016.10.001
  • Peer Reviewed
• [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] Potential roles of the wearable cardioverter-defibrillator in acute phase care of patients at high risk of sudden cardiac death: A single-center Japanese experience. (2017)
  • Author(s): Sasaki S, Shoji Y, Ishida Y, Kinjo T, Tsushima Y, Seno M, Nishizaki F, Itoh T, Izumiyama K, Yokota T, Yokoyama H, Yamada M, Horiuchi D, Kimura M, Higuma T, Tomita H, Okumura K.
  • Journal Title: J Cardiol. Volume: 69 Issue: 1 Pages: 359-363
  • DOI: 10.1016/j.jjcc.2016.08.004
  • 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 Pages: 679-688
  • 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] Effect of rivaroxaban on prothrombin fragment 1+2 compared with warfarin in patients with acute cardioembolic stroke: Insight from its serial measurement. (2016)
  • Author(s): Hagii J, Tomita H, Metoki N, Tamai Y, Saito S, Shiroto H, Hitomi H, Kamada T, Seino S, Takahashi K, Sasaki S, Yasujima M, Okumura K.
  • Journal Title: Thromb Res. Volume: 148 Pages: 9-14
  • DOI: 10.1016/j.thromres.2016.10.011
  • Peer Reviewed
• [Presentation] Blockade of Protease Activated Receptor-1 Attenuates Cardiac Hypertrophy and Fibrosis in Renin-overexpressing Hypertensive Mice. (2019)
  • Author(s): 横野良和, 成田真人, 花田賢二, 野坂匡史, 加藤朋, 工藤奈津美, 對馬迪子, 外山佑一, 妹尾麻衣子, 成田憲紀, 米倉学, 長内智宏, 富田泰史
  • Organizer: 第83回日本循環器学会学術集会
• [Presentation] Mutational Analysis of SUR2 Gene in Japanese Patients with Coronary Spastic Angina. (2019)
  • Author(s): 澁谷修司, 遠藤知秀, 西崎史恵, 花田賢二, 横山公章, 横田貴志, 富田泰史
  • Organizer: 第83回日本循環器学会学術集会
• [Presentation] p122RhoGAP/DLC-1 Overexpression Enhances Intracellular Calcium Concentration and Causes Coronary Spasm: Potential Role for Coronary Spastic Angina. (2019)
  • Author(s): 工藤奈津美, 木村嘉宏, 花田賢二, 加藤朋, 對馬迪子, 外山佑一, 横野良和, 妹尾麻衣子, 成田憲紀, 成田真人, 米倉学, 市川博章, 長内智宏, 奥村謙, 富田泰史
  • Organizer: 第83回日本循環器学会学術集会
• [Presentation] β-Arrestin 1 Negatively Regulates Intracellular Calcium Concentration in Acetylcholine M3 Receptor: Its Possible Role in Coronary Spastic Angina. (2019)
  • Author(s): 妹尾麻衣子, 花田賢二, 成田真人, 成田憲紀, 加藤朋, 工藤奈津美, 横野良和, 野坂匡史, 奥村謙, 長内智宏, 富田泰史
  • Organizer: 第83回日本循環器学会学術集会
• [Presentation] A direct factor Xa inhibitor, rivaroxaban, attenuates cardiac hypertrophy and fibrosis in renin-overexpressing hypertensive mice. (2018)
  • Author(s): Narita M, Hanada K, Yokono Y, Narita N, Senoo M, Kimura Y, Ichikawa H, Shimada M, Tanaka M, Osanai T, Okumura K, Tomita H.
  • Organizer: European Society of Cardiology Congress 2018
  • Int'l Joint Research
• [Presentation] Inhibitory Effects of Rivaroxaban, a Direct Factor Xa Inhibitor, on Cardiac Hypertrophy and Fibrosis in Renin-Overexpressing Hypertensive Mice. (2018)
  • Author(s): Narita M, Hanada K, Yokono Y, Senoo M, Narita N, Kudo N, Kato T, Nozaka M, Kawamura Y, Tanaka M, Shimada M, Osanai T, Okumura K, Tomita H.
  • Organizer: American Heart Association Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] Carvedilol Suppresses Coronary Spasm in A-Kinase Anchoring Protein 150 Knockout Mice: Its Novel Therapeutic Role in Coronary Spastic Angina. (2018)
  • Author(s): Narita N, Hanada K, Kawamura Y, Nozaka M, Kato T, Kudo N, Yokono Y, Senoo M, Narita M, Tanaka M, Osanai T, Okumura K, Tomita H.
  • Organizer: American Heart Association Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] p122RhoGAP/DLC-1 Overexpression Enhances Intracellular Calcium Concentration and Causes Coronary Spasm: Potential Role for Coronary Spastic Angina. (2018)
  • Author(s): Kudo N, Kimura Y, Hanada K, Kato T, Tsushima M, Toyama Y, Yokono Y, Senoo M, Narita N, Narita M, Yonekura M, Ichikawa H, Tanaka M, Osanai T, Okumura K, Tomita H.
  • Organizer: American Heart Association Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] レニン過剰発現マウスを用いたプロテアーゼ活性化受容体シグナル伝達抑制を介した心保護作用の検討 (2018)
  • Author(s): 横野良和、成田真人、妹尾麻衣子、成田憲紀、米倉学、花田賢二、島田美智子、 田中真実、長内智宏、富田泰史
  • Organizer: 第41回日本高血圧学会総会
• [Presentation] Rivaroxaban ameliorates hypertensive renal damage through inhibition of protease-activated receptor pathways in mice overexpressing renin (2018)
  • Author(s): 市川博章、成田真人、横野良和、加藤朋、木村嘉宏、妹尾麻衣子、成田憲紀、工藤奈津美、田中真実、長内智宏、奥村謙、富田泰史.
  • Organizer: 第82日本循環器学会学術集会
• [Presentation] p122RhoGAP/DLC-1 Overexpression Enhances Intracellular Calcium Concentration in Response to Acetylcholine in Isolated Vascular Smooth Muscle Cells. (2018)
  • Author(s): Kimura Y, Hanada K, Senoo M, Narita N, Narita M, Yonekura M, Ichikawa H, Tanaka M, Osanai T, Okumura K, Tomita H.
  • Organizer: 第82日本循環器学会学術集会
• [Presentation] A Novel Electrocardiographic Criterion for the Diagnosis of Left Ventricular Hypertrophy in the Japanese General Population. (2018)
  • Author(s): Narita M, Yamada M, Kurauchi S, Nakaji S, Tomita H.
  • Organizer: 第82日本循環器学会学術集会
• [Presentation] Involvement of Beta-arrestin-mediated Signaling in Acetylcholine M3 Receptor: Its Possible Role in Coronary Spastic Angina. (2018)
  • Author(s): Senoo M, Hanada K, Ichikawa H, Kimura Y, Narita M, Narita N, Kato T, Kudo N, YokonoY, Tanaka M, Osanai T, Okumura K, Tomita H.
  • Organizer: 第82日本循環器学会学術集会
• [Presentation] Experimental Study for Elucidating Mechanism of Coronary Spasm Using iPSC; Role of p122 RhoGAP/DLC-1 and Phospholipase C. (2018)
  • Author(s): 田中真実, 長内智宏, 奥村謙, 富田泰史.
  • Organizer: 第82日本循環器学会学術集会
• [Presentation] Disruption of A-kinase anchoring protein 150 causes coronary spasm through enhanced calcium sensitization: a potential role of microRNA-30b (2017)
  • Author(s): Nishzaki K, Tomita H, Senoo M, Narita N, Narita M, Yonekura M, Ichikawa H, Kimura Y, Tanaka M, Osanai T, Okumura K.
  • Organizer: AHA Scientific Session 2016
  • Place of Presentation: ニューオリンズ（米国）
  • Year and Date: 2017-11-12
  • Int'l Joint Research
• [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): Nishzaki K, Narita N, Senoo M, Narita M, Yonekura M, Kimura Y, Ichikawa H, Tanaka M, Osanai T, Okumura K.
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂（石川県、金沢市）
  • Year and Date: 2017-03-17
• [Presentation] Rivaroxaban ameliorates hypertensive renal damage through inhibition of protease-activated receptor pathways in mice overexpressing renin (2017)
  • Author(s): Ichikawa H, Tomita H, Narita M, Nishizaki K, Kimura Y, Senoo M, Narita N, Yonekura M, Tanaka M, Osanai T, Okumura K.
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂（石川県、金沢市）
  • Year and Date: 2017-03-17
• [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, Nishizaki K, Ichikawa H, Kimura Y, Narita N, Narita M, Yonekura M, Tanaka M, Osanai T, Okumura K, Tomita H.
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂（石川県、金沢市）
  • Year and Date: 2017-03-17
• [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, Hanada K, Senoo M, Narita N, Narita M, Yonekura M, Ichikawa H, Nishizaki K, Tanaka M, Osanai T, Okumura K.
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂（石川県、金沢市）
  • Year and Date: 2017-03-17
• [Presentation] A direct factor Xa inhibitor, rivaroxaban, attenuates cardiac hypertrophy and fibrosis in renin-overexpressing hypertensive mice (2017)
  • Author(s): Narita M, Tomita H, Okumura K.
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂（石川県、金沢市）
  • Year and Date: 2017-03-17
• [Presentation] Rivaroxaban, a direct factor Xa inhibitor, ameliorates angiotensin II-induced renal damage through inhibition of protease-activated receptor pathway-mediated inflammatory response. (2017)
  • Author(s): Ichikawa H, Narita M, Nishizaki K, Kimura Y, Seno M, Narita M, Yonekura M, Tanaka M, Shimada M, Osanai T, Tomita H.
  • Organizer: European Society of Cardiology (ESC) Congress 2017
  • Int'l Joint Research
• [Presentation] Carvedilol suppresses ST segment elevation in A-kinase anchoring protein 150 knockout mice: its novel therapeutic role in coronary spastic angina. (2017)
  • Author(s): Narita N, Hanada K, Ichikawa H, Kimura Y, Senoo M, Narita M, Yonekura M, Tanaka M, Osanai T, Okumura K, Tomita H.
  • Organizer: American Heart Association (AHA) Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] A Direct Factor Xa Inhibitor, Rivaroxaban, Attenuates Cardiac Hypertrophy and Fibrosis in Renin-overexpressing Hypertensive Mice. (2017)
  • Author(s): Narita M, Ichikawa H, Kimura Y, Senoo M, Yonekura M, Narita N, Hanada K, Shimada M, Tanaka M, Osanai T, Okumura K, Tomita H.
  • Organizer: American Heart Association (AHA) Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] Rivaroxaban, a direct factor Xa inhibitor, ameliorates angiotensin II-induced renal damage through inhibition of protease-activated receptor pathway-mediated inflammatory response. (2017)
  • Author(s): Ichikawa H, Shimada M, Narita M, Kimura Y, Senoo M, Narita N, Yonekura M, Tanaka M, Osanai T, Okumura K, Tomita H.
  • Organizer: American Heart Association (AHA) Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] p122RhoGAP/DLC-1 Overexpression Enhances Intracellular Calcium Concentration in Response to Acetylcholine in Isolated Vascular Smooth Muscle Cells (2017)
  • Author(s): Kimura Y, Hanada K, Senoo M, Narita N, Narita M, Yonekura M, Ichikawa H, Tanaka M, Okumura K, Tomita H.
  • Organizer: American Heart Association (AHA) Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] Experimental Study for Elucidating Mechanism of Coronary Spasm Using Ipsc-derived Smooth Muscle Cells; Role of P122 Rhogap / Dlc-1 and Phospholipase C (2017)
  • Author(s): Tanaka M, Osanai T, Okumura K, Tomita H.
  • Organizer: American Heart Association (AHA) Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] 第Xa因子阻害薬リバーロキサバンの高血圧性腎障害保護作用の検討 (2017)
  • Author(s): 市川博章、島田美智子、成田真人、木村嘉宏、妹尾麻衣子、成田憲紀、米倉学、田中真実、長内智宏、奥村謙、富田泰史.
  • Organizer: 第40回日本高血圧学会総会
• [Presentation] A Direct Factor Xa Inhibitor, Rivaroxaban, Attenuates Cardiac Hypertrophy and Fibrosis in Renin-overexpressing Hypertensive Mice. (2017)
  • Author(s): 成田真人、市川博章、木村嘉宏、妹尾麻衣子、米倉学、成田憲紀、花田賢二、島田美智子、田中真実、長内智宏、奥村謙、富田泰史.
  • Organizer: 第40回日本高血圧学会総会