Role of ERK2 in Ectopic Fat deposition and Cardiovascular Complications of Type II Diabetes

• Project/Area Number: 18H02815
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: National Defense Medical College
• Principal Investigator: 足立 健 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 内科学, 教授 (50231931)
• Co-Investigator(Kenkyū-buntansha): 菱木 貴子 慶應義塾大学, 医学部(信濃町), 講師 (10338022) ; 佐藤 泰司 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 生化学, 教授 (10505267) ; 井戸 康夫 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 内科学, 助教 (50814133)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2021: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2020: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2019: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2018: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: メタボリックシンドローム / ERK2 / 一酸化窒素 / インスリン抵抗性 / 内皮依存性血管拡張 / 活性酸素種 / 脂肪肝 / 異所性脂肪沈着 / 血管内皮機能 / 腎機能障害 / 脂肪細胞 / 2型糖尿病 / インスリン / 血管内皮障害 / 肥満 / 脂肪分化 / 酸化ストレス / 臓器連関 / 脂質代謝 / ２型糖尿病

Outline of Annual Research Achievements

本年度は脂肪特異的ERK2欠損マウス（AE2KO）を用いた肥満における異所性脂肪沈着の研究に著明な進展が見られた。ダパグリフロジンが異所性脂肪沈着を著明に軽減し、脂肪肝の改善とインスリン抵抗性の改善に働くことが示された。機序の一つとして骨格筋における脂肪酸酸化が改善して、ミトコンドリア機能が改善することがわかった。ミトコンドリア呼吸鎖の機能測定により、特にコハク酸投与時の酸素消費改善を認め、脂質代謝の改善に大きく寄与している事が判明した。また、脂肪組織のRNA Sequence Analysisにより、ERK2がミトコンドリアの遺伝子発現に大きく影響している可能性が示唆された。これはERK1欠損では認められず、ERK1/ERK2の間に作用点の違いがあることが示唆された。
内皮依存性ERK2欠損マウス（EE2KO）では,高脂肪食負荷において内皮依存性血管収縮因子（EDCF）放出が減少して、内皮機能改善を介してインスリン抵抗性と脂肪肝が改善する事が判明して、現在投稿中である。また、EE2KOに低酸素負荷を与えたところEDCFの低下とeNOSのuncouple改善を認め、低酸素性肺高血圧症が改善する事が判明した。これについても現在結果を集積し投稿準備中である。内皮細胞でのERK2 がeNOS Uncouplingを制御する事は、今後種々の心血管病治療につながりうる成果である。
SM22CreによるERK2欠損マウスでは血管平滑筋とともに心筋でもERK2の欠損を認めた。このマウスでは血管内皮障害のみならず、冠動脈周囲に炎症が波及して心筋症が自然発症して自然死が認められた。このマウスを用いてERK2の心筋症への関与を検討して、抗がん剤の心毒性に対して考察を加えたい。

Research Progress Status

令和3年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和3年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] ボストン大学/Vascular Biology/Metabolism Unit(米国)
• [Journal Article] Effectiveness of the d-ROMs oxidative stress test to predict long-term cardiovascular mortality. (2022)
  • Author(s): Hitomi Y, Masaki N, Ishinoda Y, Ido Y, Iwashita M, Yumita Y, Kagami K, Yasuda R, Ikegami Y, Toya T, Namba T, Nagatomo Y, Takase B, Adachi T
  • Journal Title: International Journal of Cardiology Volume: 354 Pages: 43-47
  • DOI: 10.1016/j.ijcard.2022.03.001
  • Peer Reviewed
• [Journal Article] Sarco/Endoplasmic Reticulum Ca2+ ATPase 2 Activator Ameliorates Endothelial Dysfunction; Insulin Resistance in Diabetic Mice (2022)
  • Author(s): 2)Kimura T, Kagami K, Sato A, Osaki A, Ito K, Horii S, Toya T, Masaki N, Yasuda R, Nagatomo Y, Adachi T.
  • Journal Title: Cells: Cellular Metabolism 2022 in press Volume: XXX
  • Peer Reviewed / Open Access
• [Journal Article] Deletion of Superoxide Dismutase 1 Blunted Inflammatory Aortic Remodeling in Hypertensive Mice under Angiotensin II Infusion (2021)
  • Author(s): Shiraishi Yasunaga、Ishigami Norio、Kujiraoka Takehiko、Sato Atsushi、Fujita Masanori、Ido Yasuo、Adachi Takeshi
  • Journal Title: Antioxidants (Basel). Volume: 10 Pages: 471-471
  • DOI: 10.3390/antiox10030471
  • Peer Reviewed / Open Access
• [Journal Article] Redox-dependent PPARγ/Tnpo1 complex formation enhances PPARγ nuclear localization and signaling (2020)
  • Author(s): Teratani Toshiaki、Tomita Kengo、Toma-Fukai Sachiko、Nakamura Yutaro、Itoh Toshimasa、Shimizu Hikaru、Shiraishi Yasunaga、Sugihara Nao、Higashiyama Masaaki、Shimizu Takahiko、Inoue Ikuo、Takenaka Yasuhiro、Hokari Ryota、Adachi Takeshi、Shimizu Toshiyuki、Miura Soichiro、Kanai Takanori
  • Journal Title: Free Radic Biol Med Volume: 156 Pages: 45-56
  • DOI: 10.1016/j.freeradbiomed.2020.06.005
  • Peer Reviewed / Open Access
• [Journal Article] Impact of oxidative posttranslational modifications of SERCA2 on heart failure exacerbation in young patients with non-ischemic cardiomyopathy: A pilot study (2020)
  • Author(s): Toya Takumi、Ito Kei、Kagami Kazuki、Osaki Ayumu、Sato Atsushi、Kimura Toyokazu、Horii Shunpei、Yasuda Risako、Namba Takayuki、Ido Yasuo、Nagatomo Yuji、Hayashi Katsumi、Masaki Nobuyuki、Yada Hirotaka、Adachi Takeshi
  • Journal Title: IJC Heart & Vasculature Volume: 26 Pages: 100437-100437
  • DOI: 10.1016/j.ijcha.2019.100437
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Arterial Stiffness Assessed by Cardio-Ankle Vascular Index (2019)
  • Author(s): Namba Takayuki、Masaki Nobuyuki、Takase Bonpei、Adachi Takeshi
  • Journal Title: Int J Mol Sci. Volume: 20 Pages: 3664-3664
  • DOI: 10.3390/ijms20153664
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Computed tomography-measured pulmonary artery to aorta ratio and EUTOS score for detecting dasatinib-induced pulmonary arterial hypertension (2019)
  • Author(s): Toya Takumi、Nagatomo Yuji、Kagami Kazuki、Yukino Midori、Yasuda Risako、Namba Takayuki、Ido Yasuo、Kobayashi Shinichi、Masaki Nobuyuki、Yada Hirotaka、Kimura Fumihiko、Adachi Takeshi
  • Journal Title: The International Journal of Cardiovascular Imaging Volume: 35 Pages: 1435-1442
  • DOI: 10.1007/s10554-019-01548-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Endothelial Insulin Resistance of Freshly Isolated Arterial Endothelial Cells From Radial Sheaths in Patients With Suspected Coronary Artery Disease (2019)
  • Author(s): Nobuyuki Masaki, Yasuo Ido, Toshiyuki Yamada, Youhei Yamashita, Takumi Toya, Bonpei Takase, Naomi M. Hamburg, Takeshi Adachi
  • Journal Title: J Am Heart Assoc. Volume: 8
  • DOI: 10.1161/jaha.118.010816
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Production of adeno-associated virus vectors for in vitro and in vivo applications (2019)
  • Author(s): Kimura Toyokazu、Ferran Beatriz、Tsukahara Yuko、Shang Qifan、Desai Suveer、Fedoce Alessandra、Pimentel David Richard、Luptak Ivan、Adachi Takeshi、Ido Yasuo、Matsui Reiko、Bachschmid Markus Michael
  • Journal Title: Scientific Reports Volume: 9 Pages: 13601-13601
  • DOI: 10.1038/s41598-019-49624-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The association of insulin-induced eNOS activation in freshly isolated arterial endothelial cells with cardio-ankle vascular index (2019)
  • Author(s): 5)Nobuyuki Masaki, Yasuo, Ido, Adachi T et al.
  • Journal Title: JAHA Volume: 19
  • Peer Reviewed / Open Access
• [Journal Article] 心血管病におけるSERCA2の障害 (2018)
  • Author(s): 1)足立 健、木村 豊和、東谷 卓美、伊藤 桂、長友 祐司、矢田 浩崇
  • Journal Title: 最新医学 Volume: 第73巻 Pages: 68-73
• [Journal Article] Effect of Oral Branched-Chain Amino Acids on Serum Albumin Concentration in Heart Failure Patients with Hypoalbuminemia: Results of a Preliminary Study (2018)
  • Author(s): Uchino Yuichi、Watanabe Masafumi、Takata Munenori、Amiya Eisuke、Tsushima Kensuke、Adachi Takeshi、Hiroi Yukio、Funazaki Toshikazu、Komuro Issei
  • Journal Title: American Journal of Cardiovascular Drugs Volume: 18 Pages: 327-332
  • DOI: 10.1007/s40256-018-0269-0
  • Peer Reviewed / Open Access
• [Journal Article] Preserved Vasoconstriction and Relaxation of Saphenous Vein Grafts Obtained by a No-Touch Technique for Coronary Artery Bypass Grafting (2018)
  • Author(s): Yamada T, Adachi T, Ido Y, Masaki N, Toya T, Uchimuro T, Nishigawa K, Suda H, Osako M, Yamazaki M, Takanashi S, Shimizu H
  • Journal Title: Circ J Volume: 83 Issue: 1 Pages: 232-238
  • DOI: 10.1253/circj.cj-18-0714 10.1253/circj.CJ-18-0714
  • NAID: 130007550528
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Loss of Extracellular Signal-Regulated Kinases 2 Using SM22α-Cre Driver Causes Cardiac Failure and Vascular Dysfunction、American Heart Association Scientific sessions, (2021)
  • Author(s): Kazuki Kagami, Yusuke Yumita, Midori Iwashita, Yuki Ishinoda, Takayuki Namba, Takumi Toya, Yasuo Ido, Yuji Nagatomo, Takeshi Adachi
  • Organizer: American Heart Association Scientific sessions
  • Int'l Joint Research
• [Presentation] SERCA2 C674S Modification Leads to Ca2+ Mishandling with Hypertrophy in Right Ventricular Exposed to Hypoxia (2021)
  • Author(s): Kazuki Kagami, Kei Ito, Hirotaka Yada, Yusuke Yumita, Midori Iwashita, Yuki Ishinoda, Takayuki Namba, Takumi Toya, Yasuo Ido, Yuji Nagatomo, Takeshi Adachi
  • Organizer: American Heart Association Scientific sessions
  • Int'l Joint Research
• [Presentation] Prognostic Value of Diffusion-Weighted Cardiac Magnetic Resonance Imaging in Hospitalized Heart Failure Patients (2021)
  • Author(s): Kazuki Kagami, Takumi Toya, shunpei Kuwaki, Atsushi Sato, Yusuke Yumita, Ayumu Osaki, Midori Iwashita, Risako Yasuda, Yukinori Ikegami, Takayuki Namba, Nobuyuki Masaki, Yuji Nagatomo , Katsumi Hayashi, Takeshi Adachi
  • Organizer: American Heart Association Scientific sessions
  • Int'l Joint Research
• [Presentation] Endothelial Extracellular Signal-Regulated Kinase 2 Contributed to the Development of Pulmonary Arterial Hypertension in Mice Through the Impairment of Endothelial Nitric Oxide Synthase Function (2021)
  • Author(s): Yusuke Yumita, Kazuki Kagami, Yuki Ishinoda, Midori Iwashita,Takumi Toya, Yukinori Ikegami, Takayuki Namba, Nobuyuki Masaki, Yasuo Ido, Yuji Nagatomo, Takeshi Adachi
  • Organizer: American Heart Association Scientific sessions
  • Int'l Joint Research
• [Presentation] SERCA2 C674S heterozygote knock-in mice revealed Ca2+ mishandling and hypertrophy in right ventricular under hypoxia (2021)
  • Author(s): Kazuki Kagami, Kei Ito, Hirotaka Yada, Yusuke Yumita,Yuki Ishinoda, Takayuki Namba, Takumi Toya, Yasuo Ido, Yuji Nagatomo, Takeshi Adachi
  • Organizer: 日本循環器学会学術総会
• [Presentation] Endothelial Extracellular Signal-Regulated Kinase 2 Contributed to the Development of Pulmonary Arterial Hypertension in Mice Through the Impairment of Endothelial Nitric Oxide Synthase Function (2021)
  • Author(s): Yusuke Yumita, Kazuki Kagami, Yuki Ishinoda, Midori Iwashita, Takumi Toya, Yukinori Ikegami, Takayuki Namba, Nobuyuki Masaki, Yasuo Ido, Yuji Nagatomo, Takeshi Adachi
  • Organizer: 日本循環器学会学術総会
• [Presentation] SM22α-Cre Driven Extracellular Signal-Regulated Kinase 2 Knockout Mice Causes Cardiac Failure and Vascular Dysfunction. (2021)
  • Author(s): Kazuki Kagami, Yusuke Yumita, Midori Iwashita, Yuki Ishinoda, Takayuki Namba, Takumi Toya, Risako Yasuda, Yukinori Ikegami, Nobuyuki Masaki, Yasuo Ido, Yuji Nagatomo, Takeshi Adachi
  • Organizer: The 5th JCS Council Forum on Basic CardioVascular Research
• [Presentation] 肺高血圧症における右室SERCA2 cys674の関与 (2021)
  • Author(s): 鏡 和樹、弓田 悠介、伊藤 桂 、矢田 浩崇 、石野田 悠暉、岩下 碧、東谷 卓美、難波 貴之、長友 祐司、足立 健
  • Organizer: 日本肺高血圧・肺循環学会
• [Presentation] Characterization of Tolvaptan Responder and Its Impact on the Outcome for Patients with Heart Failure in the Real World (2020)
  • Author(s): asuhiro Hitomi, Yuji Nagatomo, Kazuki Kagami, Kei Ito, Atsushi Sato, Risako Yasuda, Takayuki Nanba, Nobuyuki masaki, Hirotaka Yada, Takeshi Adachi
  • Organizer: The 84th annual meeting of the Japanese Circulation Society
• [Presentation] Adipose extracellular signal-regulated kinase 2 protected from endothelial dysfunction and the oxidative stress of perivascular adipose tissue in obese mice (2020)
  • Author(s): A Osaki , Y Sato , S Endo , K Ito, K Kagami , Y Yumita , Y Ishinoda , T Toya , Y Ido , T Namba , T Adachi
  • Organizer: The 4th JCS Council Forum on Basic CardioVascular Research
• [Presentation] Adipose ERK2 Deficiency in Obese Mice Induced Endothelial Dysfunction by Perivascular Adipose Tissue (2020)
  • Author(s): Osaki A, …Adachi T, et al
  • Organizer: 第20回NO学会学術集会 YIA
• [Presentation] SERCA2 C674S heterozygote knock-in mice leads to right ventricular failure in hypoxia (2020)
  • Author(s): Kagami K, …Adachi T,
  • Organizer: The 85th annual meeting of the Japanese Circulation Society
• [Presentation] Endothelial Extracellular Signal-Regulated Kinase 2 Contributed to the Development of Pulmonary Arterial Hypertension in Mice (2020)
  • Author(s): Yumita Y, …Adachi T,
  • Organizer: The 85th annual meeting of the Japanese Circulation Society
• [Presentation] 肥満・糖尿病における血管内皮ERK2/TP Receptor経路を介した血管内皮障害 (2020)
  • Author(s): 足立健 佐藤篤志、佐藤泰司、大崎歩、鏡和樹、難波貴之
  • Organizer: 2020年 第49回日本心脈管作動性物質 久留米
  • Invited
• [Presentation] Dysfunctional SERCA2 by the Loss of Thiol on Cys674 in Cardiovascular Diseases (2019)
  • Author(s): Takeshi Adachi
  • Organizer: 83rd Japanese Circulation Society 2019 Plenary Session 12 Frontiers of Basic Cardiovascular Research
• [Presentation] Role of Tissue-specific Extracellular Regulatory Kinase 2 in Metabolism and Endothelial Dysfunction of Obese Mice. (2019)
  • Author(s): Takeshi Adachi, Yasushi Satoh, Atsushi Sato, Kazuki Kagami
  • Organizer: 3rd Japanese Circulation Society BCVR 2019, Tokyo
  • Invited
• [Presentation] High Fat High Sucrose Diet Induced Endothelial Dysfunction, Insulin Resistance and Steatohepatosis through Superoxide Production by ERK2/TP Receptor Pathway. (2019)
  • Author(s): Atsushi Sato, Kei Ito, Kazuki Kagami, Ayumu Osaki, Takayuki Namba, Takeshi Adachi
  • Organizer: 3rd Japanese Circulation Society BCVR 2019, Tokyo YIA 優秀賞
• [Presentation] Endothelial ERK2/Thromboxane Receptor Pathway Induced Endothelial Dysfunction, Insulin Resistance and Steatohepatosis through Superoxide with High Fat High Sucrose Diet. (2019)
  • Author(s): Atsushi Sato, Yasushi Satoh, Shogo Endo, Toyokazu Kimura, Ayumu Osaki, Shunpei Horii, Kei Ito, Kazuki Kagami Takayuki Namba, Takeshi Adachi
  • Organizer: European Society of Cardiology 2019 Paris
  • Int'l Joint Research
• [Presentation] Pivotal Roles of SOD1 in Metabolism and Vascular Dysfunction in Mice with Obese (2018)
  • Author(s): Atsushi Sato
  • Organizer: 82nd Japanese Circulation Society 2018
• [Presentation] Endothelial Extracellular Signal-Regulated Kinase 2 Induced Hypertension and Endothelial Dysfunction and Insulin Resistance in Obese (2018)
  • Author(s): Atsushi Sato
  • Organizer: 82nd Japanese Circulation Society 2018
• [Presentation] Ectopic Fat Deposition with Organ Damages in Adipose Specific Extracellular Signal-Regulated Kinase 2 Deficient Mice with High Fat Diet (2018)
  • Author(s): Ayumu Osaki
  • Organizer: 82nd Japanese Circulation Society 2018
• [Presentation] Mechanism of Advantages of Preserving Perivascular Fat in the Saphenous Vein Graft Used for Coronary Artery Bypass Surgery (2018)
  • Author(s): 山田 敏之
  • Organizer: 82nd Japanese Circulation Society 2018
• [Presentation] Increased Basal eNOS Activity in Freshly Isolated Endothelial Cells from Patients with Cardiovascular Disease (2018)
  • Author(s): Nobuyuki Masaki
  • Organizer: 82nd Japanese Circulation Society 2018
• [Presentation] SERCA2 C674S heterozygote kock-in mice with angioteinsion II infusion leads to QT prologation and lethal ventricular arrhythmia due to impaired sarcoplasmic reticulum Ca2+ handling. (2018)
  • Author(s): Kei Ito
  • Organizer: European Society of Cardiology 2018
  • Int'l Joint Research
• [Presentation] Angiotensin II loading in SERCA2 C674S heterozygote knock-in mice leads to QT prolongation and lethal ventricular arrhythmia (2018)
  • Author(s): Kei Ito
  • Organizer: 日本不整脈学会総会2018 YIA 最優秀賞
• [Presentation] Adipose Extracellular Signal-Regulated Kinase 2 Protect From Ectopic Fat Depositions and Endothelial Dysfunction in Obesity. (2018)
  • Author(s): Ayumu Osaki
  • Organizer: 91th American Heart Association, Scientific Session 2018
  • Int'l Joint Research
• [Presentation] High Fat/ High Sucrose Diet Did Not Induce Endothelial Dysfunction but Impaired the Reduction of Vascular Tone with Adipose Tissue in Aortic Ring from Mice. (2018)
  • Author(s): Ayumu Osaki
  • Organizer: 91th American Heart Association, Scientific Session 2018
  • Int'l Joint Research
• [Presentation] Adipose Extracellular Signal-Regulated Kinase 2 Deficiency Impaired Endothelial Function and the Modulation of Vascular Tone with Adipose Tissue. (2018)
  • Author(s): Ayumu Osaki
  • Organizer: 91th American Heart Association, Scientific Session 2018
  • Int'l Joint Research
• [Presentation] SERCA2 C674S heterozygote knock-in mice leads to QT prolongation and lethal ventricular arrhythmia by catecholamine injection and hypertrophy with Angiotensin II. (2018)
  • Author(s): Kei Ito
  • Organizer: 91th American Heart Association, Scientific Session 2018
  • Int'l Joint Research
• [Presentation] Adipose-ERK2 Protect From Ectopic Fat Depositions and Vascular Dysfunction in Obesity (2018)
  • Author(s): Ayumu Osaki
  • Organizer: 2nd Japanese Circulation Society BCVR 2019
• [Presentation] SERCA2 C674S heterozygote knock-in mice with angiotensin infusion leads to ventricular arrhythmia (2018)
  • Author(s): Kei Ito
  • Organizer: 2nd Japanese Circulation Society BCVR 2019
• [Presentation] Activation of SERCA2 ameliorated endothelial function and skeletal muscle function of db/db mice. (2018)
  • Author(s): Toyokazu Kimura
  • Organizer: 2nd Japanese Circulation Society BCVR 2019
• [Presentation] 血管病におけるNO標的SERCA2の障害 (2018)
  • Author(s): 足立 健
  • Organizer: 2018年第71回日本酸化ストレス学会学術集会 第18回日本NO学会 合同学術集会 シンポジウム
  • Invited
• [Funded Workshop] 欧州心臓病学会 (2018)