Vascular/organ association via ERK2 in insulin resistance

• Project/Area Number: 17K09596
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: National Defense Medical College
• Principal Investigator: Takayuki Namba 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, 病院 内科, 助教 (90726499)
• Co-Investigator(Kenkyū-buntansha): 眞崎 暢之 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, 講師 (00364795) ; 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) ; 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) ; 東谷 卓美 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 (60781515)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: インスリン / メタボリックシンドローム / 2型糖尿病 / ERK2 / 一酸化窒素 / 血管内皮機能 / インスリン抵抗性 / 血管内皮細胞 / 肺高血圧 / 血管収縮因子 / 肥満 / 酸化ストレス / プロスタノイド / 二型糖尿病 / 脂肪肝 / 血管内皮障害 / 活性酸素種 / 内皮機能

Outline of Final Research Achievements

Metabolic Syndrome (Mets) is a complex disease which is characterized with insulin resistance (IR) and vascular endothelial dysfunction (ED) leading to cardiovascular diseases. The: ERK2 is the major molecule of insulin signal system. We created endothelial cell-specific deficient mice (EE2KO) and fed with high fat diet to create obese and IR model of mice. The aim of this study was to elucidate the involvement of endothelial ERK2 with IR and complications of Mets and seek the novel drug target. In EE2KO, NO synthesis was enhanced, vascular endothelial function was improved, and hypertension was suppressed. In EE2KO, IR and fatty liver were also significantly improved. A Thromboxane Receptor (TPR) was identified as the downstream of the vascular endothelial ERK2. An TPR inhibitor was administered to obese mice, and improvement similar to EE2KO was observed. The vascular endothelial ERK2 / TXA2 pathway was considered as a novel therapeutic target for Mets.

Academic Significance and Societal Importance of the Research Achievements

Metabolic Syndrome（Mets）は心臓血管病最大の危険因子である。その治療は運動、食事療法であり心血管病の特異的治療は未だ存在しない。患者さんは最終的には心筋梗塞、脳卒中などの血管病で亡くなる方が多いために、その血管病に対する特異的治療の開発は学術的にも、医学・社会学的にも大きな意義がある。マウスMetsモデルの血管ではNO作用が減弱しており、その原因として血管内皮ERK2/TXA2経路を同定した。血管特異的にこの経路を阻害することはMets血管病の新規治療につながる重要な治験と考えられた。

Research Products

• [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: International Journal of Molecular Sciences Volume: 20 Issue: 15 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 Issue: 8 Pages: 1435-1442
  • DOI: 10.1007/s10554-019-01548-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A Rare Case of Rush Progression of Purulent Pericarditis by <i>Escherichia coli</i> in a Patient with Malignant Lymphoma (2018)
  • Author(s): Horii Shunpei、Yada Hirotaka、Ito Kei、Osaki Ayumu、Sato Atsushi、Kimura Toyokazu、Yasuda Risako、Toya Takumi、Namba Takayuki、Masaki Nobuyuki、Adachi Takeshi
  • Journal Title: International Heart Journal Volume: 59 Issue: 3 Pages: 655-659
  • DOI: 10.1536/ihj.17-238
  • NAID: 130007378304
  • ISSN: 1349-2365, 1349-3299
  • Year and Date: 2018-05-31
  • Peer Reviewed
• [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): 2）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] 高脂肪高ショ糖食下における血管内皮ERK2/Thromboxane Receptor Pathwayがスーパーオキサイド産生を介して与える血管内皮機能、インスリン抵抗性および脂肪肝への影響の検討 (2019)
  • Author(s): 佐藤篤志、佐藤泰司、遠藤昌吾、木村豊和、大崎歩、堀井俊平、伊藤桂、鏡和樹、難波貴之 足立健
  • Organizer: 2019年第１９回日本NO学会 YIA 優秀賞
• [Presentation] Association of Hemodynamic Measurements Before Discharge with Lung Congestion. (2019)
  • Author(s): Takayuki Namba, Toyokazu Kimura, Risako Yasuda, Takumi Toya, Yuji Nagatomo Nobuyuki Masaki, Hirotaka Yada, Takeshi Adachi
  • Organizer: 第22回日本心不全学会 2019年 10月
• [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
• [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 Extracellular Signal-Regulated Kinase 2 Induced Hypertension and Endothelial Dysfunction and Insulin Resistance in Obese (2018)
  • Author(s): Atsushi Sato, Toyokazu Kimura, Ayumu Osaki, Shunpei Horii, Kei Ito, Takumi Tohya, Nobuyuki Masaki, Takayuki Namba Takeshi Adachi.
  • 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, Atsushi Sato, Toyokazu Kimura, Kei Ito, Takumi Tohya, Yasuo Ido, Nobuyuki Masaki, Takayuki Namba, Takeshi Adachi
  • Organizer: 82nd Japanese Circulation Society 2018
• [Presentation] Association between Total Cholesterol and Ratio of Direct to Total Bilirubin in Serum (2018)
  • Author(s): Masataka Mine, Nobuyuki Masaki, Tetsuya Hisada, Risako Yasuda, Takayuki Namba, Hirotaka Yada, Kenichi Hashimoto, Bonpei Takase, Takeshi Adachi
  • Organizer: 82nd Japanese Circulation Society 2018
• [Presentation] Histological Validation of Cardiac Magnetic Resonance T1 Mapping as an Indicator of Interstitial Myocardial Fibrosis in Non-Ischemic Cardiomyopathy Patients (2018)
  • Author(s): Takumi Toya, Nobuyuki Masaki, Katsumi Hayashi, Atsushi Sato, Ayumu Osaki, Kei Ito, Shunpei Horii, Risako Yasuda, Yasuo Ido, Takayuki Namba, Yuji Nagatomo, Hirotaka Yada, Takeshi Adachi
  • 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, Youhei Yamashita, Toshiyuki Yamada, Yasuo Ido, Risako Yasuda, Takumi Tohya, Takayuki Nanba, Yuji Nagatomo, Hirotaka Yada, Kenichi Hashimoto, Bonpei Takase, Takeshi Adachi
  • 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, Hirotaka Yada, Shunpei Horii, Takumi Toya, Yasunaga Shiraishi, Toyokazu Kimura, Ayumu Osaki, Atsushi Sato, Risako Yasuda, Takayuki Namba, Yuji Nagatomo, Nobuyuki Masaki, Yasuo Ido, Bonpei Takase, Takeshi Adachi
  • 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, Hirotaka Yada, Shunpei Horii, Takumi Toya, Yasunaga Shiraishi, Toyokazu Kimura, Ayumu Osaki, Atsushi Sato, Risako Yasuda, Takayuki Namba, Yuji Nagatomo, Nobuyuki Masaki, Yasuo Ido, Bonpei Takase, Takeshi Adachi
  • Organizer: 日本不整脈学会総会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, Yasushi Satoh, Shogo Endo, Atsushi Sato, Toyokazu Kimura, Kei Ito, Takumi Toya, Ysauo Ido, Takayuki Namba, Takeshi Adachi
  • 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, Atsushi Sato, Toyokazu Kimura, Shunpei Horii, Kei Ito, Takumi Toya, Ysauo Ido, Nobuyuki Masaki, Takayuki Namba, Takeshi Adachi
  • 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, Yasushi Satoh, Shogo Endo, Atsushi Sato, Toyokazu Kimura, Kei Ito, Takumi Toya, Ysauo Ido, Takayuki Namba, Takeshi Adachi
  • 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, Hirotaka Yada, Shunpei Horii, Takumi Toya, Yasunaga Shiraishi, Toyokazu Kimura, Ayumu Osaki, Atsushi Sato, Risako Yasuda, Takayuki Namba, Yuji Nagatomo, Nobuyuki Masaki, Yasuo Ido, Bonpei Takase, Takeshi Adachi
  • Organizer: 91th American Heart Association, Scientific Session 2018
  • Int'l Joint Research
• [Presentation] Pivotal roles of SOD1 in metabolism and vascular dysfunction in mice with obese. (2018)
  • Author(s): Takeshi Adachi, Atsushi Sato, Yasunaga Shiraishi, Ayumu Osaki, Toyokazu Kimura, Syunpei Horii, Kei Ito, Takumi Toya, Nobuyuki Masaki, Yasuo Ido
  • Organizer: 日本循環器学会総会 (JCS) 2018
  • Int'l Joint Research
• [Presentation] Adipose Specific Extracellular Signal-Regulated Kinase 2 suppresses Ectopic Fat and limit Organ Damage in Obese (2018)
  • Author(s): Ayumu Osaki, Atsushi Sato, Toyokazu Kimura, Shunpei Horii, Kei Ito, Takumi Toya, Nobuyuki Masaki ,Takayuki Namba, Takeshi Adachi
  • Organizer: 日本循環器学会総会 (JCS) 2018
  • Int'l Joint Research
• [Presentation] Endothelial Extracellular Signal-Regulated Kinase 2 induced Hypertension and Endothelial Dysfunction and Insulin Resistance in Obese (2018)
  • Author(s): Atsushi Sato, Yasushi Satoh, Shogo Endo, Toyokazu Kimura, Ayumu Osaki, Shunpei Horii, Kei Ito, Takayuki Namba, Takesshi Adachi
  • Organizer: 日本循環器学会総会 (JCS) 2018
  • Int'l Joint Research
• [Presentation] Endothelial Extracellular Signal-Regulated Kinase 2 Increases Blood Pressure and Induced Endothelial Dysfunction and Insulin Resistance in Mice with High Fat High Sucrose Diet (2017)
  • Author(s): Atsushi Sato, Yasushi Satoh, Endo XXXX, Toyokazu Kimura, Ayumu Osaki, Shunpei Horii, Kei Ito, Takayuki Namba, Takeshi Adachi
  • Organizer: AHA Scientific Session 2017
  • Int'l Joint Research
• [Presentation] The mechanism of lean body in SOD1 deficient mice with High Fat High Sucrose Diet: The role of activated AMP-Activated Protein Kinase with Oxidative Stress. (2017)
  • Author(s): Atsushi Sato, Yasunaga Shiraishi, Ayumu Osaki, Toyokazu Kimura, Takumi Toya, Risako Yasuda, Takayuki Namba, Hirotaka Yada, Nobuyuki Masaki, Takeshi Adachi
  • Organizer: AHA Scientific Session 2017
  • Int'l Joint Research