MLC phosphatase plays an important role in cardiac function and fibrosis

• Project/Area Number: 19K08578
• 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: Mie University
• Principal Investigator: Okamoto Ryuji 三重大学, 医学部附属病院, 教授 (60378346)
• Co-Investigator(Kenkyū-buntansha): 伊藤 正明 三重大学, 医学系研究科, 学長 (00223181) ; 土肥 薫 三重大学, 医学系研究科, 教授 (50422837)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 心肥大 / 心不全 / ねじれ運動 / ミオシン軽鎖 / 心筋症 / ミオシン

Outline of Research at the Start

本研究では心筋ミオシンのリン酸化制御が心臓のねじれ運動を制御していると仮定し、ラットを用いたストレインエコーによるねじれ運動の解析と、分子生物学的にMLC2vのリン酸化レベルの定量を行い、その関連を明らかにする。様々な心不全モデルを作成し、薬剤介入時のねじれ運動の変化とMLC2vシグナルの変化を検討する。さらに、MLC2vホスファターゼのTgおよびKOマウスを用いることで、MLC2vのリン酸化レベルを生体で上下させ、ねじれ運動の異常の有無を解析すると共に、MLC2vのリン酸化異常がどのように心肥大・心不全・心筋症の発症に結びつくか、その分子メカニズムを明らかにする。

Outline of Final Research Achievements

To examine the effect of deletion of myosin light chain phosphatase (MLCP) in heart, we developed cardiomyocyte-specific deletion knockout mice of MYPT2, myosin phosphatase target subunit 2 (c-MYPT2-/- mice). After aldosterone treatment, c-MYPT2-/- mice could preserve cardiac systolic and diastolic function better than wild-type mice. These results were accompanied with decreased collagen tissue growth factor (CTGF) and decreased cardiac fibrosis. Both MYPT2 and CTGF were increased in HL-1 cardiomyocytes after treatment of aldosterone (Ald). After knockdown of MYPT2, CTGF induction was prevented in HL-1 cells treated with Ald.

Academic Significance and Societal Importance of the Research Achievements

心筋ミオシン軽鎖(MLC)の変異は、ヒトの肥大型心筋症の原因の１つで、MLCキナーゼは日本人の家族性拡張型心筋症の１原因である。このため、MLCのリン酸化レベルを制御することは、心不全の治療に応用できる可能性が高い。MLCホスファターゼのTGマウスは、DCM様の病態を示すが、MLCホスファターゼKOマウスは、心臓の線維化を抑制することが今回明らかとなった。MLCのリン酸化レベルの微調整が、心機能や線維化に重要な働きを担っていると考えられた。一方で、MLCホスファターゼはMLC以外も基質を持つ可能性があり、今回アルドステロン刺激下で、直接的にCTGFの発現を制御している可能性が示唆された。

Research Products

• [Journal Article] A hyperaldosteronism subtypes predictive model using ensemble learning (2023)
  • Author(s): Karashima S, Kawakami M, Nambo H, Kometani M, Kurihara I, Ichijo T, Katabami T, Tsuiki M, Wada N, Oki K, Ogawa Y, Okamoto R, Tamura K, Inagaki N, Yoshimoto T, Kobayashi H, Kakutani M, Fujita M, Izawa S, Suwa T, Kamemura K, Yamada M, Tanabe A, Naruse M, Yoneda T; JPAS/JRAS Study Group.
  • Journal Title: Scientific Reports Volume: 13 Issue: 1
  • DOI: 10.1038/s41598-023-29653-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Associated factors and effects of comorbid atrial fibrillation in hypertensive patients due to primary aldosteronism (2023)
  • Author(s): Sakaguchi S, Okamoto R, Inoue C, Akao M, Kamemura K, Kurihara I, Takeda Y, Ohno Y, Inagaki N, Rakugi H, Katabami T, Tsuiki M, Tanabe A, Tamura K, Fujita S, Yano Y, Dohi K; JRAS investigators; Naruse M.
  • Journal Title: Journal of Human Hypertension Volume: - Issue: 9 Pages: 757-766
  • DOI: 10.1038/s41371-022-00753-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Moyamoya Disease Complicating Ebstein's Anomaly (2022)
  • Author(s): Goto Itaru、Okamoto Ryuji、Sato Yu、Tsuji Akihiro、Tanigawa Takashi、Dohi Kaoru
  • Journal Title: Internal Medicine Volume: 61 Issue: 24 Pages: 3683-3686
  • DOI: 10.2169/internalmedicine.9516-22
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2022-12-15
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Perihilar Variant of Focal Segmental Glomerulosclerosis Due to <i>De novo</i> Branchio-oto-renal Syndrome (2022)
  • Author(s): Saiki R, Katayama K, Kitano M, Tsujimoto K, Tanaka F, Suzuki Y, Murata T, Kurita T, Okamoto R, Takeuchi K, Dohi K.
  • Journal Title: Internal Medicine Volume: 61 Issue: 13 Pages: 2033-2038
  • DOI: 10.2169/internalmedicine.8508-21
  • NAID: 130008124756
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2022-07-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prevalence and Clinical Characteristics of Proximal Deep Venous Thrombosis After a High-Density Coronavirus Disease 2019 Cluster in a Japanese Psychiatric Hospital (2022)
  • Author(s): Sato Toru、Ogihara Yoshito、Fujimoto Naoki、Usami Akihiro、Hamaguchi Tatsuya、Tanabe Masaki、Okamoto Ryuji、Nakase Shinji、Dohi Kaoru
  • Journal Title: Circulation Journal Volume: 86 Issue: 3 Pages: 458-463
  • DOI: 10.1253/circj.CJ-21-0987
  • NAID: 130008163882
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2022-02-25
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endovascular Treatment for Lower-extremity Arterial Thrombosis in a Patient with Congenital Afibrinogenemia and a History of Bleeding Complications (2022)
  • Author(s): Hiramatsu Daisuke、Ogihara Yoshito、Matsumoto Takeshi、Sato Kei、Takasaki Akihiro、Kurita Tairo、Okamoto Ryuji、Wada Hideo、Dohi Kaoru
  • Journal Title: Internal Medicine Volume: 61 Issue: 3 Pages: 361-364
  • DOI: 10.2169/internalmedicine.7542-21
  • NAID: 130008150387
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2022-02-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Thrombotic Microangiopathy Due to Severe Hypertension in a Patient With Primary Aldosteronism (2022)
  • Author(s): Hirabayashi Yosuke、Okamoto Ryuji、Miura Shoko、Inoue Chisa、Uemura Mei、Sugino Yuichi、Murata Tomohiro、Katayama Kan、Yano Yutaka、Sakuma Hajime、Dohi Kaoru
  • Journal Title: Circulation Journal Volume: 86 Issue: 2 Pages: 334
  • DOI: 10.1253/circj.CJ-21-0653
  • NAID: 130008144233
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2022-01-25
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Elderly Man With “Overalls” Edema (2022)
  • Author(s): Nakaya Hitoshi、Okamoto Ryuji、Nagashima Kazunori、Sugino Yuichi、Ogihara Yoshito、Sakuma Hajime、Dohi Kaoru
  • Journal Title: Circulation Journal Volume: 86 Issue: 2 Pages: 333
  • DOI: 10.1253/circj.CJ-21-0700
  • NAID: 130008144240
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2022-01-25
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cardiac Fibrosis: Chronic Inflammatory Disease and Promising Therapeutic Target (2022)
  • Author(s): Okamoto Ryuji
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 15 Pages: 8074-8074
  • DOI: 10.3390/ijms23158074
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Perinatal hypoxia aggravates occlusive pulmonary vasculopathy in SU5416/hypoxia-treated rats later in life (2022)
  • Author(s): Oshita H, Sawada H, Mitani Y, Tsuboya N, Kabwe JC, Maruyama J, Yusuf A, Ito H, Okamoto R, Otsuki S, Yodoya N, Ohashi H, Oya K, Kobayashi Y, Kobayashi I, Dohi K, Nishimura Y, Saitoh S, Maruyama K, Hirayama M
  • Journal Title: Am J Physiol Lung Cell Mol Physiol. 2022 Aug 1;323(2):L178-L192. Volume: 323 Issue: 2 Pages: 178-192
  • DOI: 10.1152/ajplung.00422.2021
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Arrhythmogenic right ventricular cardiomyopathy complicating hypertrophic cardiomyopathy (2022)
  • Author(s): Kagawa Yoshihiko、Okamoto Ryuji、Asano Yoshihiro、Sakata Yasushi、Dohi Kaoru
  • Journal Title: European Heart Journal - Cardiovascular Imaging Volume: 23 Issue: 9 Pages: e326-e326
  • DOI: 10.1093/ehjci/jeac103
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CRISPR-mediated Bmpr2 point mutation exacerbates late pulmonary vasculopathy and reduces survival in rats with experimental pulmonary hypertension (2022)
  • Author(s): Kabwe JC, Sawada H, Mitani Y, Oshita H, Tsuboya N, Zhang E, Maruyama J, Miyasaka Y, Ko H, Oya K, Ito H, Yodoya N, Otsuki S, Ohashi H, Okamoto R, Dohi K, Nishimura Y, Mashimo T, Hirayama M, Maruyama K.
  • Journal Title: Respir Res. Volume: ;23 Issue: 1 Pages: 1-22
  • DOI: 10.1186/s12931-022-02005-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serum-Induced Expression of Brain Natriuretic Peptide Contributes to Its Increase in Patients with HFpEF (2022)
  • Author(s): Okamoto Ryuji、Hashizume Ryotaro、Suzuki Noboru、Ito Rie、Tokuhara Tomoko、Fujiwara Hiroshi、Zhe Ye、Ito Hiromasa、Abe Takaya、Dohi Kaoru
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 6 Pages: 2991-2991
  • DOI: 10.3390/ijms23062991
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cardiorenal protective effects of sodium-glucose cotransporter 2 inhibition in combination with angiotensin II type 1 receptor blockade in salt-sensitive Dahl rats. (2022)
  • Author(s): Ito H, Okamoto R, Ali Y, Zhe Y, Katayama K, Ito M, Dohi K.
  • Journal Title: J Hypertens. Volume: 40 Issue: 5 Pages: 956-968
  • DOI: 10.1097/hjh.0000000000003099
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Regulation of myosin light-chain phosphorylation and its roles in cardiovascular physiology and pathophysiology (2022)
  • Author(s): Ito Masaaki、Okamoto Ryuji、Ito Hiromasa、Zhe Ye、Dohi Kaoru
  • Journal Title: Hypertension Research Volume: 45 Issue: 1 Pages: 40-52
  • DOI: 10.1038/s41440-021-00733-y
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Generation of Transgenic Mice that Conditionally Overexpress Tenascin-C (2021)
  • Author(s): Yonebayashi Saori、Tajiri Kazuko、Hara Mari、Saito Hiromitsu、Suzuki Noboru、Sakai Satoshi、Kimura Taizo、Sato Akira、Sekimoto Akiyo、Fujita Satoshi、Okamoto Ryuji、Schwartz Robert J.、Yoshida Toshimichi、Imanaka-Yoshida Kyoko
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 620541-620541
  • DOI: 10.3389/fimmu.2021.620541
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gap junction protein beta 4 plays an important role in cardiac function in humans, rodents, and zebrafish (2020)
  • Author(s): Okamoto Ryuji、Goto Itaru、Nishimura Yuhei、Kobayashi Issei、Hashizume Ryotaro、Yoshida Yoshinori、Ito Rie、Kobayashi Yuhko、Nishikawa Misato、Ali Yusuf、Saito Shunsuke、Tanaka Toshio、Sawa Yoshiki、Ito Masaaki、Dohi Kaoru
  • Journal Title: PLOS ONE Volume: 15 Issue: 10 Pages: 0240129-0240129
  • DOI: 10.1371/journal.pone.0240129
  • Peer Reviewed / Open Access
• [Journal Article] BNP as a Major Player in the Heart-Kidney Connection. (2019)
  • Author(s): Okamoto R, Ali Y, Hashizume R, Suzuki N, Ito M.
  • Journal Title: Int J Mol Sci. Volume: 20 Issue: 14 Pages: 3581-3581
  • DOI: 10.3390/ijms20143581
  • Peer Reviewed / Open Access
• [Presentation] The Regulation of Myosin Light Chain Phosphorylation Plays an Important Role in the Development of Cardiac Fibrosis in MR-Related Hypertension (2023)
  • Author(s): Zhe Ye
  • Organizer: 日本循環器学会総会
  • Int'l Joint Research
• [Presentation] Associated factors and effects of comorbid atrial fibrillation in hypertensive patients due to primary aldosteronism (2023)
  • Author(s): Shintaro Sakaguchi, Ryuji Okamoto, Masaharu Akao, Kohei Kamemura, Hiromi Rakugi, Satoshi Fujita, Kaoru Dohi; JRAS investigators; Mitsuhide Naruse
  • Organizer: 日本循環器学会総会
  • Int'l Joint Research