Transferrin receptor1 and cardiovascular disease

• Project/Area Number: 16K09273
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General internal medicine(including psychosomatic medicine)
• Research Institution: Hyogo Medical University
• Principal Investigator: NAITO Yoshiro 兵庫医科大学, 医学部, 講師 (10446049)
• Co-Investigator(Kenkyū-buntansha): 増山 理 兵庫医科大学, 医学部, 教授 (70273670)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 循環器 / トランスフェリン受容体 / 慢性腎臓病 / 鉄 / 内科学 / 高血圧症 / 心血管病 / 高血圧 / 内科 / 臨床

Outline of Final Research Achievements

Iron is an essential mineral in the body, while excessive iron increases the oxidative stress. Intracellular iron metabolism is regulated by transferrin receptor 1 (TfR1). We investigated the role of iron and TfR1 on the development of cardiovascular diseases by experimental studies. As results, we found iron deposition in hypertensive hypertrophied heart, hypertensive kidney, and aortic aneurysm in mouse. In addition, TfR1 heterozygous deleted mice exhibited attenuated the extent of hypertrophied heart, renal fibrosis, and aortic aneurysm, along with reduced iron deposition and oxidative stress as compared to wild-type mice.

Academic Significance and Societal Importance of the Research Achievements

高血圧は、現在国民の1/3が罹患している最も多い生活習慣病である。高血圧は自覚症状が少ないが、自覚症状が出現した時には脳卒中や心筋梗塞など生命に関わる疾患が進行していることが多く、国民の生命予後に大きく影響している。
本研究では、高血圧の病態を鉄過剰という新たな観点から検討し、心血管病の病態形成における鉄及び細胞内鉄取り込み受容体トランスフェリン受容体1（Transferrin Receptor 1: TfR1）の関与を基礎研究より明らかにした。本研究成果は高血圧、心血管病の新規予防及び治療法開発に寄与するため、学術的意義、社会的意義は高いと考える。

Research Products

• [Journal Article] Influence of dietary iron intake restriction on the development of hypertension in weanling prehypertensive rats (2018)
  • Author(s): Okuno K, Naito Y, Yasumura S, Sawada H, Oboshi M, Nishimura K, Asakura M, Ishihara M, Masuyama T
  • Journal Title: Heart and Vessels Volume: 33 Issue: 7 Pages: 820-825
  • DOI: 10.1007/s00380-018-1134-4
  • Peer Reviewed
• [Journal Article] Altered expression of intestinal duodenal cytochrome b and divalent metal transporter 1 might be associated with cardio-renal anemia syndrome (2017)
  • Author(s): Naito Y, Sawada H, Oboshi M, Okuno K, Yasumura S, Okuhara Y, Eguchi A, Nishimura K, Soyama Y, Asakura M, Ishihara M, Tsujino T, Masuyama T
  • Journal Title: Heart and Vessels Volume: 32 Issue: 11 Pages: 1410-1414
  • DOI: 10.1007/s00380-017-1013-4
  • Peer Reviewed
• [Journal Article] Iron-restricted pair-feeding affects renal damage in rats with chronic kidney disease (2017)
  • Author(s): Yoshiro Naito, Aya Senchi, Hisashi Sawada, Makiko Oboshi, Tetsuo Horimatsu, Keisuke Okuno, Seiki Yasumura, Masaharu Ishihara, Tohru Masuyama
  • Journal Title: PLoS One Volume: 12 Issue: 2 Pages: e0172157-e0172157
  • DOI: 10.1371/journal.pone.0172157
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Attenuation of hypertension and renal damage in renovascular hypertensive rats by iron restriction. (2016)
  • Author(s): Oboshi M, Naito Y, Sawada H, Iwasaku T, Okuhara Y, Eguchi A, Hirotani S, Mano T, Tsujino T, Masuyama T.
  • Journal Title: Hypertens Res Volume: 39 Issue: 12 Pages: 832-839
  • DOI: 10.1038/hr.2016.93
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Iron regulating system in cardio-renal anemia syndrome (2018)
  • Author(s): Naito T, Masuyama T
  • Organizer: 第63回日本透析医学会学術集会・総会
  • Invited
• [Presentation] 循環器疾患と鉄 (2018)
  • Author(s): 内藤由朗、増山 理
  • Organizer: 第66回日本心臓病学会学術集会
  • Invited
• [Presentation] 高血圧性臓器障害と鉄 (2018)
  • Author(s): 内藤由朗
  • Organizer: 第54回高血圧関連疾患モデル学会学術総会
  • Invited
• [Presentation] Heterozygous Deletion of Transferrin Receptor 1 Suppresses Angiogenesis in a Mouse Model of Hind Limb Ischemia (2018)
  • Author(s): Okuno K, Naito Y, Yasumura S, Sawada H,Nishimura K, Asakura M, Ishihara M, Masuyama T.
  • Organizer: Arteriosclerosis, Thrombosis and Vascular Biology/Peripheral Vascular Disease (ATVB/PVD) 2018
  • Int'l Joint Research
• [Presentation] Effective Hemoglobin Level for the Prevention of All-cause Mortality is Different between Male and Female Patients with Heart Failure with Preserved Ejection Fraction (2018)
  • Author(s): Okuno K, Naito Y, Asakura M, Sugahara M, Ando T, Nagai T, Saito Y, Yoshikawa T, Masuyama T, Anzai T.
  • Organizer: American Heart Association Scientific Sessions 2018
  • Int'l Joint Research
• [Presentation] Transferrin receptor 1 is associated with the development of diabetic kidney disease (2018)
  • Author(s): Yasumura S, Naito Y, Okuno K, Nishimura K, Asakura M, Ishihara M, Masuyama T.
  • Organizer: The 2nd JCS Council Forum on Basic Cardio Vascular Research
  • Int'l Joint Research
• [Presentation] Iron Metabolism in a Mouse Model of Hind Limb Ischemia (2018)
  • Author(s): Okuno K, Naito Y, Yasumura S, Nishimura K, Asakura M, Ishihara M, Masuyama T.
  • Organizer: The 2nd JCS Council Forum on Basic Cardio Vascular Research
  • Int'l Joint Research
• [Presentation] Dietary iron restriction suppressed the development of hypertension in weanling prehypertensive rats (2018)
  • Author(s): Okuno K, Naito Y, Yasumura S, Nishimura K, Asakura M, Ishihara M, Masuyama T
  • Organizer: The 1st JCS Council Forum on Basic Cardio Vascular Research
• [Presentation] Cellular iron transport in renal fibrosis (2018)
  • Author(s): 康村誠希, 内藤由朗, 奥野圭佑, 朝倉正紀, 石原正治, 増山 理
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Iron and Renal Fibrosis in Experimental Renal Injury (2017)
  • Author(s): Yoshiro Naito, Makiko Oboshi, Hisashi Sawada, Keisuke Okuno, Seiki Yasumura, Yoshitaka Okuhara, Akiyo Eguchi, Koichi Nishimura, Yuko Soyama, Masaharu Ishihara, and Tohru Masuyama
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂他 （石川県、金沢市）
  • Year and Date: 2017-03-17
• [Presentation] A Novel Mice Model of Stress Induced Cardiomyopathy Revealed that MAPK Pathway Has an Important Role in Transient LV Dysfunction (2017)
  • Author(s): Yuko Soyama, Toshiaki Mano, Yoshiro Naito, Akiko Goda, Masaharu Ishihara, Tohru Masuyama
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂他 （石川県、金沢市）
  • Year and Date: 2017-03-17
• [Presentation] Iron and Renal Fibrosis in Experimental Renal Injury (2017)
  • Author(s): Naito Y, Oboshi M, Sawada H, Okuno K, Yasumura S, Okuhara Y, Eguchi A, Nishimura K, Soyama Y, Ishihara M, Masuyama T
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] 高齢者心不全と貧血 (2017)
  • Author(s): 内藤由朗, 奥野圭佑, 康村誠希, 朝倉正紀, 増山 理
  • Organizer: 第21回日本心不全学会学術集会
  • Invited
• [Presentation] A Novel Mice Model of Stress Induced Cardiomyopathy Revealed that MAPK Pathway Has an Important Role in Transient LV Dysfunction (2017)
  • Author(s): Soyama Y, Mano T, Naito Y, Goda A, Ishihara M, Masuyama T
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] Differential prognostic impact of anemia in male and female patients with heart failure with preserved ejection fraction: analysis of Japanese Heart Failure Syndrome with Preserved Ejection Fraction(JASPER) study (2017)
  • Author(s): Okuno K, Naito Y, Asakura M, Sugahara M, Ando T, Nagai T, Saito Y, Yoshikawa T, Masuyama T, Anzai T
  • Organizer: European Society of Cardiology Congress 2017
  • Int'l Joint Research
• [Presentation] 心腎貧血連関における十二指腸鉄吸収蛋白の関与 (2017)
  • Author(s): 康村誠希, 内藤由朗, 大星真貴子, 奥野圭佑, 奥原祥貴, 安藤友孝, 西村晃一, 織原良行, 朝倉正紀, 増山 理
  • Organizer: 第21回日本心不全学会学術集会
• [Presentation] Differential prognostic impact of anemia in 75 years or older male and female patients with heart failure with preserved ejection fraction: analysis of japanese heart failure syndrome with preserved ejection fraction (JASPER) study (2017)
  • Author(s): Okuno K, Naito Y, Asakura M, Sugahara M, Ando T, Nagai T, Saito Y, Yoshikawa T, Masuyama T, Anzai T
  • Organizer: American Heart Association Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] MAPK pathway plays an important role in a novel mice model of stress induced cardiomyopathy (2017)
  • Author(s): Soyama Y, Naito Y, Goda A, Okuhara Y, Nishimura K, Oboshi M, Orihara Y, Okuno K, Yasumura S, Asakura M, Ishihara M, Masuyama T
  • Organizer: American Heart Association Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] Exercise Training Improves Left Ventricular Remodeling via Increase of the CD4+CD25+Foxp3+ Regulatory T Cells in Murine Heart Failure After Myocardial Infarction (2016)
  • Author(s): Akiyo Eguchi, Toshihiro Iwasaku, Yoshitaka Okuhara, Makiko Oboshi, Yoshiro Naito, Toshiaki Mano, Tohru Masuyama, Shinichi Hirotani
  • Organizer: American Heart Association Scientific Sessions 2016
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] 高血圧患者における食事性鉄制限の有用性の検討 (2016)
  • Author(s): 内藤 由朗, 大星 真貴子, 澤田 悠, 辻野 健, 増山 理
  • Organizer: 第39回日本高血圧学会総会
  • Place of Presentation: 仙台国際センター （宮城県、仙台市）
  • Year and Date: 2016-09-30
• [Presentation] 心不全における鉄吸収システム（シンポジウム） (2016)
  • Author(s): 内藤由朗，澤田 悠, 大星真貴子, 石原正治，増山 理
  • Organizer: 第64回日本心臓病学会学術集会
  • Place of Presentation: 東京国際フォーラム （東京都、千代田区）
  • Year and Date: 2016-09-23
• [Presentation] ラットを用いた血管病変の検討（シンポジウム） (2016)
  • Author(s): 内藤由朗，増山 理
  • Organizer: 第48回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 京王プラザホテル（東京都、新宿区）
  • Year and Date: 2016-07-14
  • Invited
• [Presentation] 本態性高血圧症に対する食事性鉄制限の試み (2016)
  • Author(s): 内藤 由朗, 大星 真貴子, 澤田 悠 , 安藤 友孝, 廣谷 信一, 真野 敏昭 , 石原 正治, 増山 理
  • Organizer: 第113回日本内科学会講演会
  • Place of Presentation: 東京国際フォーラム （東京都、千代田区）
  • Year and Date: 2016-04-15