MR関連高血圧症による心不全発症メカニズムの解明

• Project/Area Number: 22K08098
• 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: 岡本 隆二 三重大学, 医学部附属病院, 教授 (60378346)
• Co-Investigator(Kenkyū-buntansha): 土肥 薫 三重大学, 医学系研究科, 教授 (50422837)
• Project Period (FY): 2022-04-01 – 2025-03-31
• Project Status: Granted (Fiscal Year 2023)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2024: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2022: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 心肥大 / 心不全 / ミオシン軽鎖 / ミネラルコルチコイド受容体 / アルドステロン / 心筋症 / 高血圧 / ねじれ運動

Outline of Research at the Start

MR関連高血圧症および心筋障害が注目されている。高血圧症の第一選択薬はカルシウム拮抗薬、ACEi/ARB、サイアザイド利尿薬であるが、それにMR拮抗薬(MRA)を追加した際、有意に降圧効果や心血管イベントの予防効果が得られる症例が多く、MR関連高血圧症と命名され、注目されている。一方高アルドステロン血症患者において、Rhoキナーゼ/ミオシン軽鎖(MLC)ホスファターゼシグナルが活性化していることが最近明らかとなった。本研究では、MR関連高血圧症による心肥大・線維化・心不全において、MLCシグナルの異常がどのように関与しているか、その分子メカニズムを明らかにする。

Outline of Annual Research Achievements

野生型マウスおよび心臓特異的ミオシン軽鎖(MLC)ホスファターゼKOマウスを用いて、片腎摘出後、アルドステロンの慢性投与を行い、MR関連高血圧症における心不全モデルを作成し、心肥大および心臓の線維化の解析を行った。
心臓特異的MLCホスファターゼKOマウスは野生型に比較し、心臓収縮能および拡張能が保たれ、組織学的にも心臓の線維化が抑制されていた。
また心臓特異的MLCホスファターゼKOマウスでは結合組織成長因子(CTGF)の低下を認めた。
HL1心筋細胞をアルドステロンで刺激すると、MLCホスファターゼ・サブユニットのMYPT2およびCTGFの両方が増加した。一方、心筋MLCキナーゼ(cMLCK)はアルドステロン刺激により濃度依存性に減少した。これはMLCのリン酸化レベルも低下も伴っており、アルドステロン刺激により、MLCホスファターゼとcMLCKのバランスにより、MLCのリン酸化レベルが制御されていることが明らかとなった。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

動物モデルの作成・解析に加え、培養細胞を用いた検討でも、一定の成果を得ることが出来ているため。

Strategy for Future Research Activity

マウスにおける心エコーのストレイン解析や、細胞でのノックダウン下でのアルドステロン刺激により、アルドステロンの心毒性におけるMLCシグナルの分子メカニズムと病態を明らかにする。

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 Pages: 3043-3043
  • DOI: 10.1038/s41598-023-29653-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Letter by Okamoto et al Regarding Article, “Restoration of Cardiac Myosin Light Chain Kinase Ameliorates Systolic Dysfunction by Reducing Superrelaxed Myosin” (2023)
  • Author(s): Okamoto Ryuji、Ye Zhe、Dohi Kaoru
  • Journal Title: Circulation Volume: 148 Issue: 25 Pages: 2073-2073
  • DOI: 10.1161/circulationaha.123.066090
  • Peer Reviewed / Open Access
• [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] Associated factors and effects of comorbid atrial fibrillation in hypertensive patients due to primary aldosteronism (2022)
  • 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] 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 / Open Access / 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
• [Presentation] The Regulation of Myosin Light Chain Phosphorylation Plays an Important Role in the Development of Cardiac Fibrosis in MRRelated Hypertension (2023)
  • Author(s): Zhe Ye, Ryuji Okamoto, Hiromasa Ito, Rie Ito, Mizuki Ida, Masaaki Ito, Kaoru Dohi
  • 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 Rakugi5, Satoshi Fujita, Kaoru Dohi; JRAS investigators; Mitsuhide Naruse
  • Organizer: 日本循環器学会総会
  • Int'l Joint Research
• [Presentation] Cardiac-specific deletion of myosin phosphatase targeting subunit 2 alleviates cardiac fibrosis in mineralocorticoid receptor-related hypertension (2023)
  • Author(s): Zhe Ye, Ryuji Okamoto, Hiromasa Ito, Moriwaki Keishi, Rie Ito, Mizuki Ida, Masaaki Ito, Kaoru Dohi
  • Organizer: ヨーロッパ心臓病学会(ESC)
• [Presentation] Cardiac-specific knockout of myosin phosphatase targeting subunit 2 prevents cardiac fibrosis in a connective tissue growth factor‐dependent manner in mineralocorticoid receptor-related hypertension mice (2023)
  • Author(s): Zhe Ye, Ryuji Okamoto, Hiromasa Ito, Moriwaki Keishi, Rie Ito, Mizuki Ida, Masaaki Ito, Kaoru Dohi
  • Organizer: アメリカ心臓協会学会(AHA）
  • Int'l Joint Research
• [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, Ryuji Okamoto, Hiromasa Ito, Rie Ito, Mizuki Ida, Masaaki Ito, Kaoru Dohi
  • 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 Rakugi5, Satoshi Fujita, Kaoru Dohi; JRAS investigators; Mitsuhide Naruse
  • Organizer: 日本循環器学会総会
  • Int'l Joint Research
• [Presentation] Predictors and effects of comorbid atrial fibrillation in hypertensive patients due to primary aldosteronism (2022)
  • Author(s): Shintaro Sakaguchi, Ryuji Okamoto, Chisa Inoue, Kohei Kamemura, Isao Kurihara, Yoshiyu Takeda, Youichi Ohno, Hiromi Rakugi, Takuyuki Katabami, Akiyo Tanabe, Kouichi Tamura, Fujita Satoshi, Yutaka Yano, Kaoru Dohi and Mitsuhide Naruse ,JPAS/JRAS Study Group
  • Organizer: 国際高血圧学会(ISH)
  • Int'l Joint Research