Elucidation of Inflammation Mechanism for Muscle Wasting Treatment in Chronic Heart Failure

• Project/Area Number: 16K16607
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied health science
• Research Institution: Juntendo University
• Principal Investigator: Kadoguchi Tomoyasu 順天堂大学, 医学(系)研究科(研究院), 博士研究員 (10762049)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 筋萎縮 / 酸化ストレス / NADPH oxidase / アンジオテンシンII / 心不全 / 骨格筋 / 活性酸素種 / NADPH Oxidase / 炎症 / NADPH oxidase 4 / 骨格筋萎縮 / ミトコンドリア

Outline of Final Research Achievements

We examined whether NADPH oxidase 4 (NOX4) is associated with muscle wasting in Ang II-infusion mice. Either saline or Ang II was infused into WT and Nox4 KO mice via osmotic minipump for 4 weeks. At 4 weeks after Ang II-infusion, body and skeletal muscle weight, and myocyte cross-sectional area significantly decreased in WTA mice compared to WTV mice. These changes were significantly attenuated in KOA mice. Protein degradation and synthesis markers in skeletal muscle significantly increased and decreased in WTA mice compared to WTV mice, respectively. Moreover, NF-E2-related factor 2 (Nrf2) regulated genes and protein expression level of Nrf2 in nuclear fraction significantly decreased in WTA mice compared to WTV mice. These parameters were significantly ameliorated in KOA mice (all p values <0.05). NOX4 induces muscle wasting by Ang II via downregulation of Nrf2 pathway, suggesting that the NOX4-Nrf2 axis plays an essential role in the development of muscle wasting.

Academic Significance and Societal Importance of the Research Achievements

これまで、NOX4由来のROSは肺疾患および腎疾患の病態発症・進展における役割が示されてきたが、心不全による骨格筋萎縮におけるNOX4およびNrf2の役割は明らかではなかった。本研究では、NOX4欠損マウスを用いることにより、心不全における骨格筋萎縮に対するNOX4およびNrf2の役割が明らかとなる。NOX4由来のROSによるNrf2低下が、心不全における骨格筋萎縮に関与する可能性に着目した研究は、国内外では取り組みがない。したがって、骨格筋におけるNOX4由来のROS適正化は、心不全における骨格筋萎縮の治療の可能性を模索するものである。

Research Products

• [Journal Article] Inhibition of interleukin-1 suppresses angiotensin II-induced aortic inflammation and aneurysm formation. (2018)
  • Author(s): Isoda K, Akita K, Kitamura K, Sato-Okabayashi Y, Kadoguchi T, Isobe S, Ohtomo F, Sano M, Shimada K, Iwakura Y, Daida H
  • Journal Title: Int J Cardiol Volume: 270 Pages: 221-227
  • DOI: 10.1016/j.ijcard.2018.05.072
  • Peer Reviewed / Open Access
• [Journal Article] Correlation of Nutritional Indices on Admission to the Coronary Intensive Care Unit with the Development of Delirium (2018)
  • Author(s): Sugita Yurina、Miyazaki Tetsuro、Shimada Kazunori、Shimizu Megumi、Kunimoto Mitsuhiro、Ouchi Shohei、Aikawa Tatsuro、Kadoguchi Tomoyasu、Kawaguchi Yuko、Shiozawa Tomoyuki、Takasu Kiyoshi、Hiki Masaru、Takahashi Shuhei、Sumiyoshi Katsuhiko、Iwata Hiroshi、Daida Hiroyuki
  • Journal Title: Nutrients Volume: 10 Issue: 11 Pages: 1712-1712
  • DOI: 10.3390/nu10111712
  • Peer Reviewed / Open Access
• [Journal Article] Possible Role of NADPH Oxidase 4 in Angiotensin II-Induced Muscle Wasting in Mice (2018)
  • Author(s): Kadoguchi Tomoyasu、Shimada Kazunori、Koide Hiroshi、Miyazaki Tetsuro、Shiozawa Tomoyuki、Takahashi Shuhei、Aikawa Tatsuro、Ouchi Shohei、Kitamura Kenichi、Sugita Yurina、Hamad Al Shahi、Kunimoto Mitsuhiro、Sato-Okabayashi Yayoi、Akita Koji、Isoda Kikuo、Daida Hiroyuki
  • Journal Title: Frontiers in Physiology Volume: 9 Pages: 1-9
  • DOI: 10.3389/fphys.2018.00340
  • Peer Reviewed / Open Access
• [Journal Article] Deletion of NAD(P)H Oxidase 2 Prevents Angiotensin II-Induced Skeletal Muscle Atrophy (2018)
  • Author(s): Kadoguchi Tomoyasu、Takada Shingo、Yokota Takashi、Furihata Takaaki、Matsumoto Junichi、Tsuda Masaya、Mizushima Wataru、Fukushima Arata、Okita Koichi、Kinugawa Shintaro
  • Journal Title: BioMed Research International Volume: 2018 Pages: 1-10
  • DOI: 10.1155/2018/3194917
  • NAID: 120006406686
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An Interleukin-6 Receptor Antibody Suppresses Atherosclerosis in Atherogenic Mice. (2017)
  • Author(s): Akita K, Isoda K, Sato-Okabayashi Y, Kadoguchi T, Kitamura K, Ohtomo F, Shimada K, Daida H.
  • Journal Title: Front Cardiovasc Med Volume: 4 Pages: 84-91
  • DOI: 10.3389/fcvm.2017.00084
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Low 1,5-anhydroglucitol levels are associated with long-term cardiac mortality in acute coronary syndrome patients with hemoglobin A1c levels less than 7.0% (2017)
  • Author(s): Ouchi Shohei、Shimada Kazunori、Miyazaki Tetsuro、Takahashi Shuhei、Sugita Yurina、Shimizu Megumi、Murata Azusa、Kadoguchi Tomoyasu、Kato Takao、Aikawa Tatsuro、Suda Shoko、Sai Eiryu、Hiki Masaru、Iwata Hiroshi、Kasai Takatoshi、Miyauchi Katsumi、Daida Hiroyuki
  • Journal Title: Cardiovascular Diabetology Volume: 16 Issue: 1 Pages: 1-9
  • DOI: 10.1186/s12933-017-0636-1
  • Peer Reviewed / Open Access
• [Journal Article] Left Atrial Appendage Volume and Plasma Docosahexaenoic Acid Levels Are Associated With Atrial Fibrillation Recurrence After Catheter Ablation (2017)
  • Author(s): Shiozawa Tomoyuki、Shimada Kazunori、Sekita Gaku、Hayashi Hidemori、Tabuchi Haruna、Miura Seiji、Fujimoto Shinichiro、Kadoguchi Tomoyasu、Ouchi Shohei、Aikawa Tatsuro、Al Shahi Hamad、Takahashi Shuhei、Miyazaki Tetsuro、Sumiyoshi Masataka、Nakazato Yuji、Daida Hiroyuki
  • Journal Title: Cardiology Research Volume: 8 Issue: 3 Pages: 96-104
  • DOI: 10.14740/cr542w
  • Peer Reviewed / Open Access
• [Journal Article] Low Serum Levels of EPA are Associated with the Size and Growth Rate of Abdominal Aortic Aneurysm (2017)
  • Author(s): 44.Aikawa T, Miyazaki T, Shimada K, Sugita Y, Shimizu M, Ouchi S, Kadoguchi T, Yokoyama Y, Shiozawa T, Hiki M, Takahashi S, Al Shahi H, Dohi S, Amano A, Daida H
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 24 Issue: 9 Pages: 912-920
  • DOI: 10.5551/jat.38315
  • NAID: 130006038434
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access
• [Journal Article] Pioglitazone improves whole-body aerobic capacity and skeletal muscle energy metabolism in patients with metabolic syndrome (2017)
  • Author(s): Yokota T, Kinugawa S, Hirabayashi K, Suga T, Takada S, Omokawa M, Kadoguchi T, Takahashi M, Fukushima A, Matsushima S, Yamato M, Okita K, Tsutsui H
  • Journal Title: J Diabetes Investig Volume: 印刷中 Issue: 4 Pages: 1-6
  • DOI: 10.1111/jdi.12606
  • NAID: 120006337767
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dipeptidyl peptidase-4 inhibitor improved exercise capacity and mitochondrial biogenesis in mice with heart failure via activation of GLP-1 receptor signaling. (2016)
  • Author(s): Takada S, Masaki Y, Kinugawa S, Matsumoto J, Furihata T, Mizushima W, Kadoguchi T, Fukushima A, Homma T, Takahashi M, Harashima S, Matsushima S, Yokota T, Tanaka S, Okita K, Tsutsui H
  • Journal Title: Cardiovasc Res Volume: 111 Issue: 4 Pages: 338-347
  • DOI: 10.1093/cvr/cvw182
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Low and exacerbated levels of 1,5-anhydroglucitol are associated with cardiovascular events in patients after first-time elective percutaneous coronary intervention. (2016)
  • Author(s): Takahashi S, Shimada K, Miyauchi K, Miyazaki T, Sai E, Ogita M, Tsuboi S, Tamura H, Okazaki S, Shiozawa T, Ouchi S, Aikawa T, Kadoguchi T, Al Shahi H, Yoshihara T, Hiki M, Isoda K, Daida H.
  • Journal Title: Cardiovasc Diabetol Volume: 15
  • Peer Reviewed / Open Access
• [Presentation] Angiotensin II-dependent Activation of NADPH Oxidase 4 Contributes to Muscle Wasting in Mice via Downregulation of NF-E2-related Factor 2 (2018)
  • Author(s): Kadoguchi T, Shimada K, Miyazaki T, Aikawa T, Ouchi S, Kitamura K, Kunimoto M, Sugita Y, Shiozawa T, Isoda K, Daida H
  • Organizer: European Society of Congress 2018
  • Int'l Joint Research
• [Presentation] Malnutrition and Low Omega 6 Pufa Levels on Admission Affect the Development of Delirium in Patients With Acute Cardiovascular Disease Admitted to Coronary Care Unit (2018)
  • Author(s): Sugita Y, Miyazaki T, Shimada K, Shimizu M, Kunimoto M, Aikawa T, Ouchi S, Kadoguchi T, Kawaguchi Y, Shiozawa T, Takasu K, Hiki M, Takahashi S, Yokoyama M, Iwata H, Daida H
  • Organizer: American Heart Association 2018 Scientific Session
  • Int'l Joint Research
• [Presentation] 心不全における心筋および骨格筋炎症に対する自発運動の効果の検討 (2018)
  • Author(s): 門口智泰, 島田和典, Hamad Al Shahi, 國本充洋, 代田浩之
  • Organizer: 第73回日本体力医学会大会
• [Presentation] 筋萎縮におけるNADPH Oxidase 4およびNF-E2-related factor 2の役割の検討 (2018)
  • Author(s): 門口智泰, 島田和典, 喜多村健一, 相川達郎, 大内翔平, 國本充洋, 横山美帆, 杉田有里那, 宮崎哲朗, 代田浩之
  • Organizer: 第24回日本心臓リハビリテーション学会学術集会
• [Presentation] アンジオテンシンIIによる筋萎縮におけるNADPH oxidaseの働き (2018)
  • Author(s): 門口智泰, 島田和典, 小出 寛, 宮崎哲朗,相川達郎, 大内翔平, 塩澤知之, 高橋秀平, 喜多村健一, 國本充洋, 杉田有里那, 秋田耕嗣, 磯田菊生, 代田浩之
  • Organizer: 第6回骨格筋生物学研究会
• [Presentation] Angiotensin II-Induced Muscle Wasting is Regulated by NADPH Oxidase 4-Derived Oxidative Stress via NF-E2 Related Factor (2018)
  • Author(s): 門口智泰, 島田和典, 宮崎哲朗, 塩澤知之, 高橋秀平, 相川達郎, 大内翔平, 喜多村健一, 杉田有里那, 國本充洋, 佐藤弥生, 磯田菊生, 代田浩之.
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Short-term Methotrexate Treatment Prevents Aortic Aneurysm Progression and Macrophage Infiltration in Mouse Models of Abdominal Aortic Aneurysms (2018)
  • Author(s): 大内翔平, 宮﨑哲朗, 島田和典, 杉田有里那, 門口智泰, 清水めぐみ, 相川達郎, 塩澤知之, 比企 優, 髙橋秀平, 代田浩之.
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Circulating Levels of Follistatin-like 1 are Associated with Cardiovascular Events in Patients Undergoing Elective Percutaneous Coronary Intervention with Drug-eluting Stents (2018)
  • Author(s): Aikawa T, Shimada K, Miyauchi K, Miyazaki T, Tsai R, Ouchi S, Kadoguchi T, Kunimoto M, Joki Y, Dohi T, Okazaki S, Isoda K, Ohhashi K, Shibata R, Murohara T, Ouchi N, Daida H.
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Deletion of NADPH Oxidase 4 Ameliorates Skeletal Muscle Atrophy in Angiotensin II-Infusion Mice (2017)
  • Author(s): Kadoguchi T, Shimada K, Shiozawa T, Takahashi S, Hamad Al Shahi, Aikawa T, Ouchi S, Sugita Y, Kitamura K, Akita K, Miyazaki T, Isoda K, Daida H
  • Organizer: Cell Symposia Exercise Metabolism
  • Int'l Joint Research
• [Presentation] NADPH Oxidase 4 Induces Muscle Wasting via Regulation of NF-E2-Related Factor 2 in Angiotensin II-Infusion Mice (2017)
  • Author(s): Kadoguchi T, Shimada K, Shiozawa T, Takahashi S, Hamad Al Shahi, Aikawa T, Ouchi S, Sugita Y, Kitamura K, Akita K, Miyazaki T, Isoda K, Daida H
  • Organizer: European Society of Cardiology 2017
  • Int'l Joint Research
• [Presentation] An Anti-Interleukin-1β Antibody Suppresses Both Angiotensin II-induced Renal Inflammation and Hypertension. (2017)
  • Author(s): Kitamura K, Isoda K, Akita K, Okabayashi Y, Kadoguchi T, Shimada K, Daida H
  • Organizer: American Heart Association Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] 自発運動が心筋梗塞による心筋および骨格筋炎症におよぼす影響の検討 (2017)
  • Author(s): 門口智泰，島田和典, Hamad Al Shahi, 塩澤知之, 高橋秀平, 相川達郎, 大内翔平, 横山美帆, 喜多村健一, 宮崎哲朗, 代田浩之
  • Organizer: 第23回日本心臓リハビリテーション学会学術集会
• [Presentation] 酸化ストレス産生源であるNADPH Oxidase 4はアンジオテンシンII誘発性の筋萎縮を制御する (2017)
  • Author(s): 門口智泰，島田和典, 駒野悠太, 代田浩之
  • Organizer: 第72回日本体力医学会大会
• [Presentation] Inhibition of NAD(P)H oxidase 4 ameliorates Angiotensin II-induced protein degradation via improving mitochondrial dysfunction in skeletal myocytes (2016)
  • Author(s): Kadoguchi T, Shimada K, Shiozawa T, Takahashi S, Hamad Al Shahi , Aikawa T, Ouchi S, Sugita Y, Miyazaki T, Akita K, Isoda K, Daida H
  • Organizer: American Heart Association Scientific Session 2016
  • Place of Presentation: アメリカ、ニューオリンズ
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] NAD(P)H oxidase 4 plays a key role in Angiotensin II-induced protein degradation in skeletal muscle cells (2016)
  • Author(s): Kadoguchi T, Shimada K, Shiozawa T, Takahashi S, Hamad Al Shahi , Miyazaki T, Akita K, Isoda K, Daida H
  • Organizer: European Society of Cardiology Congress 2016.
  • Place of Presentation: イタリア、ローマ
  • Year and Date: 2016-08-27
  • Int'l Joint Research