Role of calcium/calmodulin-dependent protein kinase II and development of new treatment strategy for coronary spastic angina

• Project/Area Number: 19K08530
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Hirosaki University
• Principal Investigator: Tomita Hirofumi 弘前大学, 医学研究科, 教授 (00431437)
• Co-Investigator(Kenkyū-buntansha): 花田 賢二 弘前大学, 医学部附属病院, 助教 (90632993)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
• Keywords: 冠攣縮 / カルシウム / カルモジュリンキナーゼ

Outline of Research at the Start

従来の冠攣縮機序解明を目的とした研究は、血管平滑筋細胞内カルシウムイオン濃度上昇の亢進に基づき進められてきた。しかし最近我々は、細胞内カルシウムイオン濃度の上昇を伴わない新たな機序を見出した。本研究では冠攣縮の新しい機序としてのカルシウム感受性亢進の関与を、その中心となるカルモジュリンキナーゼII との関連において明らかにする。さらにカルシウム感受性亢進を抑制するとされるカルベジロールの冠攣縮抑制効果を検討し、動物実験ならびにiPS細胞技術を用いてその機序を明らかにする。本研究によりカルシウム拮抗薬治療抵抗性の難治性冠攣縮性狭心症の機序解明ならびにその治療法開発への応用が期待される。

Outline of Final Research Achievements

In the present study, we demonstrated the inhibitory effects of carvedilol and diltiazem on coronary spasm in mouse models of coronary spastic angina. Furthermore, we performed in vitro experiments to further investigate its mechanism, and found intracellular signaling pathways and a novel molecule associated with coronary spasm. The present study may help better understand mechanism of the coronary spasm and contribute to the development of a novel treatment strategy for coronary spastic angina.

Academic Significance and Societal Importance of the Research Achievements

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。冠攣縮性狭心症の治療薬としてカルシウム拮抗薬が用いられているものの、カルシウム拮抗薬抵抗性の難治性冠攣縮性狭心症患者も少なくなく、治療に難渋する場合も多い。本研究により冠攣縮性狭心症の新しい機序解明のみならず、カルシウム拮抗薬治療抵抗性の難治性冠攣縮性狭心症の機序解明ならびにその治療法開発への応用が期待される。

Research Products

• [Journal Article] Reduced Left Ventricular Ejection Fraction Is a Risk for Sudden Cardiac Death in the Early Period After Hospital Discharge in Patients With Acute Myocardial Infarction (2022)
  • Author(s): Hanada K, Sasaki S, Seno M, Kimura Y, Ichikawa H, Nishizaki F, Yokoyama H, Yokota T, Okumura K, Tomita H.
  • Journal Title: Circulation Journal Volume: 86 Issue: 10 Pages: 1490-1498
  • DOI: 10.1253/circj.CJ-21-0999
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2022-09-22
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced β-adrenergic response in mice with dominant-negative expression of the PKD2L1 channel. (2022)
  • Author(s): Murakami M, Murakami AM, Nemoto T, Ohba T, Yonekura M, Toyama Y, Tomita H, Matsuzaki Y, Sawamura D, Hirota K, Itagaki S, Asada Y, Miyoshi I.
  • Journal Title: PLoS One Volume: 17 Issue: 1 Pages: 0261668-0261668
  • DOI: 10.1371/journal.pone.0261668
  • Peer Reviewed / Open Access
• [Journal Article] A Novel Risk Stratification System for Ischemic Stroke in Japanese Patients With Non-Valvular Atrial Fibrillation (2021)
  • Author(s): Okumura K, Tomita H, Nakai M, Kodani E, Akao M, Suzuki S, Hayashi K, Sawano M, Goya M, Yamashita T, Fukuda K, Ogawa H, Tsuda T, Isobe M, Toyoda K, Miyamoto Y, Miyata H, Okamura T, Sasahara Y; J-RISK AF Research Group.
  • Journal Title: Circulation Journal Volume: 85 Issue: 8 Pages: 1254-1262
  • DOI: 10.1253/circj.CJ-20-1075
  • NAID: 130008066730
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2021-07-21
  • Peer Reviewed
• [Journal Article] Rivaroxaban attenuates cardiac hypertrophy by inhibiting protease-activated receptor-2 signaling in renin-overexpressing hypertensive mice. (2021)
  • Author(s): Narita M, Hanada K, Kawamura Y, Ichikawa H, Sakai S, Yokono Y, Senoo M, Narita N, Shimada M, Osanai T, Okumura K, Tomita H.
  • Journal Title: Hypertens Res Volume: 44 Issue: 10 Pages: 1261-1273
  • DOI: 10.1038/s41440-021-00700-7
  • Peer Reviewed
• [Journal Article] Diltiazem inhibits coronary spasm via inhibition of Cav1.2 phosphorylation and protein kinase C activation in a mouse model of coronary spastic angina (2021)
  • Author(s): Ishida Y, Kitayama K, Hanada K, Shibutani S, Nishizaki K, Kinjo T, Endo T, Suzuki A, Tateyama S, Nishizaki F, Sukekawa T, Tanaka M, Osanai T, Okumura K, Tomita H.
  • Journal Title: International Heart Journal Volume: -
  • NAID: 130008069198
  • Peer Reviewed / Open Access
• [Journal Article] Persistent or permanent atrial fibrillation is associated with severe cardioembolic stroke in patients with non-valvular atrial fibrillation (2021)
  • Author(s): Hagii J, Metoki N, Saito S, Shiroto H, Sasaki S, Takahashi K, Hitomi H, Baba Y, Yamada N, Seino S, Kamada T, Uchizawa T, Nakamura T, Yasujima M, Tomita H.
  • Journal Title: Thrombosis Journal Volume: 19 Issue: 1 Pages: 22-22
  • DOI: 10.1186/s12959-021-00276-9
  • Peer Reviewed / Open Access
• [Journal Article] Rivaroxaban attenuates cardiac hypertrophy via inhibition of protease-activated receptor-2 signaling in renin-overexpressing hypertensive mice (2021)
  • Author(s): Narita M, Hanada K, Kawamura Y, Ichikawa H, Sakai S, Yokono Y, Senoo M, Narita N, Shimada M, Osanai T, Okumura K, Tomita H.
  • Journal Title: Hypertension Research Volume: -
  • Peer Reviewed
• [Journal Article] N-Terminal Pro–B-Type Natriuretic Peptide as a Risk Biomarker for Stroke in a General Japanese Population (2020)
  • Author(s): Tomita Hirofumi
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 27 Issue: 8 Pages: 749-750
  • DOI: 10.5551/jat.ED127
  • NAID: 130007883645
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2020-08-01
  • Peer Reviewed
• [Journal Article] Trends in Prevalence of Non-Valvular Atrial Fibrillation and Anticoagulation Therapy in a Japanese Region ― Analysis Using the National Health Insurance Database ― (2020)
  • Author(s): Narita Noritomo、Okumura Ken、Kinjo Takahiko、Mikami Joko、Tsushima Katsuko、Takahashi Reiko、Noro Makiko、Hashimoto Ayaka、Sasaki Teiko、Takaki Misaki、Ishidoya Emiko、Narita Yurika、Imai Hideno、Ono Emiko、Tomita Hirofumi
  • Journal Title: Circulation Journal Volume: 84 Issue: 5 Pages: 706-713
  • DOI: 10.1253/circj.CJ-18-0989
  • NAID: 130007835084
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2020-04-24
  • Peer Reviewed
• [Journal Article] Blockade of PAR-1 Signaling Attenuates Cardiac Hypertrophy and Fibrosis in Renin-Overexpressing Hypertensive Mice (2020)
  • Author(s): Yokono Y, Hanada K, Narita M, Tatara Y, Kawamura Y, Miura N, Kitayama K, Nakata M, Nozaka M, Kato T, Kudo N, Tsushima M, Toyama Y, Itoh K, Tomita H.
  • Journal Title: Journal of the American Heart Association Volume: 9 Issue: 12
  • DOI: 10.1161/jaha.119.015616
  • Peer Reviewed / Open Access
• [Journal Article] D-dimer and C-reactive Protein as Potential Biomarkers for Diagnosis of Trousseau's Syndrome in Patients with Cerebral Embolism (2020)
  • Author(s): Tsushima Michiko、Metoki Norifumi、Hagii Joji、Saito Shin、Shiroto Hiroshi、Yasujima Minoru、Kato Tomo、Kudo Natsumi、Toyama Yuichi、Yokono Yoshikazu、Nozaka Masashi、Kawamura Yosuke、Nakata Masamichi、Tomita Hirofumi
  • Journal Title: Journal of Stroke and Cerebrovascular Diseases Volume: 29 Issue: 2 Pages: 104534-104534
  • DOI: 10.1016/j.jstrokecerebrovasdis.2019.104534
  • Peer Reviewed
• [Journal Article] Mutational analysis of β-arrestin in Japanese patients with coronary spastic angina (2020)
  • Author(s): Kudo N, Hanada K, Kawamura Y, Nakata M, Nozaka M, Kitayama K, Miura N, Tanaka M, Osanai T, Tomita H.
  • Journal Title: Hirosaki Medical Journal Volume: 70 Pages: 139-147
  • NAID: 130007818299
  • Peer Reviewed / Open Access
• [Journal Article] Novel Electrocardiographic Criteria for the Diagnosis of Left Ventricular Hypertrophy in the Japanese General Population (2019)
  • Author(s): Narita Masato、Yamada Masahiro、Tsushima Michiko、Kudo Natsumi、Kato Tomo、Yokono Yoshikazu、Toyama Yuichi、Senoo Maiko、Yonekura Manabu、Narita Noritomo、Kimura Yoshihiro、Sawada Kaori、Tokuda Itoyo、Tomita Hirofumi
  • Journal Title: International Heart Journal Volume: 60 Issue: 3 Pages: 679-687
  • DOI: 10.1536/ihj.18-511
  • NAID: 130007655750
  • ISSN: 1349-2365, 1349-3299
  • Year and Date: 2019-05-30
  • Peer Reviewed
• [Journal Article] IQGAP1 activates PLC‐δ1 by direct binding and moving along microtubule with DLC‐1 to cell surface (2019)
  • Author(s): Tanaka Makoto、Osanai Tomohiro、Homma Yoshimi、Hanada Kenji、Okumura Ken、Tomita Hirofumi
  • Journal Title: FASEB BioAdvances Volume: 1 Issue: 8 Pages: 465-480
  • DOI: 10.1096/fba.2019-00020
  • Peer Reviewed / Open Access
• [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
• [Presentation] p122RhoGAP/DLC-1 overexpression enhances intracellular calcium concentration via increase in calcium release from endoplasmic reticulum: its potential role in coronary spastic angina (2022)
  • Author(s): Kimura Y, Tsushima M, Senoo M, Ichikawa H, Nishizaki F, Yokoyama H, Yokota T, Tomita H.
  • Organizer: 第86回日本循環器学会学術集会
• [Presentation] Genetic variants of DAG and IP3 signaling pathways involved in predisposition to severe cases of coronary spastic angina (2022)
  • Author(s): Shibutani S, Yonekura M, Shikanai S, Nozaka M, Kawamura Y, Ichikawa H, Kasai S, Shimizu E, Hanada K, Yokoyama H, Yokota T, Higuma T, Yoshida Y, Imoto S, Okumura K, Itoh K, Tomita H.
  • Organizer: 第86回日本循環器学会学術集会
• [Presentation] Possible protective effects of SCH79797, a protease-activated receptor-1 antagonist, on renal impairment in renin-overexpressing hypertensive mice (2022)
  • Author(s): Sorimachi Y, Hanada K, Shimada M, Shikanai S, Sakai S, Hamaura S, Yamazaki K, Kitayama K, Nagawa D, Hamadate M, Miura N, Tomita H.
  • Organizer: 第86回日本循環器学会学術集会
• [Presentation] Esaxerenone, a novel mineralocorticoid receptor blocker, reduces albuminuria in renin-overexpressing hypertensive mice with high salt intake (2022)
  • Author(s): Sakai S, Hanada K, Shimada M, Shikanai S, Sorimachi Y, Hamaura S, Yamazaki K, Kitayama K, Nagawa D, Hamadate M, Miura N, Tomita H.
  • Organizer: 第86回日本循環器学会学術集会
• [Presentation] p122RhoGAP/DLC-1 overexpression enhances intracellular calcium concentration via increase in calcium release from endoplasmic reticulum: a potential role for coronary spastic angina (2020)
  • Author(s): Kimura Y, Yamada N , Hanada K, Ichikawa H, Tanaka M, Osanai T, Okumura K, Tomita H.
  • Organizer: 第85回日本循環器学会学術集会
• [Presentation] Carvedilol suppresses coronary spasm in A-kinase anchoring protein 150 knockout mice : a possible role of CaMKII in coronary spastic angina (2020)
  • Author(s): Kitayama K, Nagawa D, Miura N, Hamadate M, Kawamura Y, Nakata M, Nozaka M, Hanada K, Tomita H.
  • Organizer: 第85回日本循環器学会学術集会
• [Presentation] Effect of Non-selective β-adrenergic receptor blocker Carvedilol for Coronary Spasm (2020)
  • Author(s): Nozaka M, Hanada K, Kawamura Y, Nakata M, Kitayama K, Nagawa D, Miura N, Hamadate M, Osanai T, Tomita H.
  • Organizer: 第85回日本循環器学会学術集会
• [Presentation] Possible protective effects of SGLT2 inhibitor empagliflozin on renal impairment in renin-overexpressing hypertensive transgenic mice (2020)
  • Author(s): Kawamura Y, Hanada K, Shimada M, Sakai S, Sorimachi Y, Shikanai S, Hamaura S, Yamazaki K, Kitayama K, Nagawa D, Hamadate M, Miura N, Nozaka M, Nakata M, Osanai T, Tomita H.
  • Organizer: 第85回日本循環器学会学術集会
• [Presentation] 冠攣縮性狭心症と遺伝子 (2019)
  • Author(s): 富田泰史
  • Organizer: 第67回日本心臓病学会学術集会
  • Invited
• [Presentation] Recent advances in the pathogenesis of coronary spasm: Roles of phospholipase C-d1 and its related proteins (2019)
  • Author(s): 富田泰史
  • Organizer: 第3回日本循環器学会基礎研究フォーラム
  • Invited
• [Presentation] Blockade of protease activated receptor-1 signaling attenuates cardiac hypertrophy and fibrosis in renin-overexpressing hypertensive mice (2019)
  • Author(s): Yokono Y, Narita M, Kawamura Y, Kato T, Kudo N, Tsushima M, Toyama Y, Hanada K, Shimada M, Makoto T, Osanai T, Tomita H
  • Organizer: European Society of Cardiology (ESC) Congress 2019
  • Int'l Joint Research
• [Presentation] プロテアーゼ活性化受容体シグナル抑制による心保護作用の検討 (2019)
  • Author(s): 横野良和、成田真人、花田賢二、島田美智子、田中真実、長内智宏、富田泰史
  • Organizer: 第40回日本循環制御医学会総会・学術集会
• [Presentation] Deficiency of p62/SQSTM1 Exacerbates Doxorubicin-induced Cardiac Dysfunction (2019)
  • Author(s): Tsushima M, Mimura J, Liu J, Yamazaki H, Kasai S, Tomita H, Itoh K
  • Organizer: American Heart Association (AHA) Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] Ca 拮抗薬の中断によって引き起こされた急性心筋梗塞、難治性の異型狭心症の一例 (2019)
  • Author(s): 川村陽介、相馬宇伸、遠藤知秀、西崎史恵、花田賢二、横山公章、横田貴志、山田雅大、富田泰史
  • Organizer: 第169回日本循環器学会東北地方会