The effects of renin-angiotensin system control by HIF-1alpha in arteriosclerosis formation

• Project/Area Number: 25860063
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pharmacology in pharmacy
• Research Institution: The University of Tokushima
• Principal Investigator: ISHIZAWA Keisuke 徳島大学, ヘルスバイオサイエンス研究部, 教授 (60398013)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 血管リモデリング / 動脈硬化 / 血管平滑筋 / Hypoxia inducible factor / アンジオテンシンII / 酸化ストレス / 血管内皮 / HIF-1α / アンジオテンシンII受容体 / hypoxia-inducible factor / レニン－アンジオテンシン系

Outline of Final Research Achievements

Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor which regulates expression levels of a lot of genes implicated in cell proliferation, differentiation, angiogenesis, and so on. Recently, several reports have shown that angiotensin II (Ang II) and cytokines can also induce HIF-1α without hypoxic condition, and thus some reports have suggested that HIF-1α plays crucial roles in chronic inflammation. We have elucidated that Ang II-induced vascular remodeling is suppressed by smooth muscle cell (SMC)-specific HIF-1α deficiency. In our study, we showed that SMC-derived HIF-1α contributes to Ang II-induced vascular smooth muscle cell migration, proliferation and hypertrophy, and vascular fibrosis. We suggested that Ang II-induced SMC-derived HIF-1α expression also contributes to activation of Ang II-AT1 receptor signaling axis. The feedback regulation by HIF-1α may play key roles in Ang II-AT1-induced vascular remodeling.

Research Products

• [Journal Article] Nitrosonifedipine ameliorates the progression of type 2 diabetic nephropathy by exerting antioxidative effects. (2014)
  • Author(s): Ishizawa K, Izawa-Ishizawa Y, Yamano N, Urushihara M, Sakurada T, Imanishi M, Fujii S, Nuno A, Miyamoto L, Kihira Y, Ikeda Y, Kagami S, Kobori H, Tsuchiya K, Tamaki T.
  • Journal Title: PLoS One. Volume: 9(1) Issue: 1 Pages: 86335-86335
  • DOI: 10.1371/journal.pone.0086335
  • Peer Reviewed / Open Access
• [Journal Article] Iron chelation by deferoxamine prevents renal interstitial fibrosis in mice with unilateral ureteral obstruction. (2014)
  • Author(s): Ikeda Y, Ozono I, Tajima S, Imao M, Horinouchi Y, Izawa-Ishizawa Y, Kihira Y, Miyamoto L, Ishizawa K, Tsuchiya K, Tamaki T.
  • Journal Title: PLoS One. Volume: 9 Issue: 2 Pages: e89355-e89355
  • DOI: 10.1371/journal.pone.0089355
  • Peer Reviewed / Open Access
• [Journal Article] Smooth muscle cell-specific Hif-1α deficiency suppresses angiotensin II-induced vascular remodelling in mice. (2014)
  • Author(s): Imanishi M, Tomita S, Ishizawa K, Kihira Y, Ueno M, Izawa-Ishizawa Y, Ikeda Y, Yamano N, Tsuchiya K, Tamaki T.
  • Journal Title: Cardiovasc Res Volume: in press Issue: 3 Pages: 460-468
  • DOI: 10.1093/cvr/cvu061
  • Peer Reviewed / Open Access
• [Journal Article] Deletion of Hypoxia-Inducible Factor-1α in Adipocytes Enhances Glucagon-Like Peptide-1 Secretion and Reduces Adipose Tissue Inflammation (2014)
  • Author(s): Yoshitaka KIHIRA, Mariko MIYAKE, Manami HIRATA, Yoji HOSHINA, Kana KATO, Hitoshi SHIRAKAWA, Hiroshi SAKAUE, Noriko YAMANO, Yuki IZAWA-ISHIZAWA, Keisuke ISHIZAWA, Yasumasa IKEDA, Koichiro TSUCHIYA, Toshiaki TAMAKI, Shuhei TOMITA
  • Journal Title: PLOS ONE Volume: 9 Issue: 4 Pages: e93856-e93856
  • DOI: 10.1371/journal.pone.0093856
  • Peer Reviewed / Open Access
• [Journal Article] HIF-2α/ARNT complex regulates hair development via induction of p21Waf1/Cip1 and p27Kip1. (2014)
  • Author(s): Imamura Y, Tomita S, Imanishi M, Kihira Y, Ikeda Y, Ishizawa K, Tsuchiya K, Tamaki T.
  • Journal Title: FASEB J Volume: in press Issue: 6 Pages: 2517-2524
  • DOI: 10.1096/fj.13-244079
  • Peer Reviewed / Open Access
• [Journal Article] Drug development for cardiorenal disease based on oxidative stress control (2014)
  • Author(s): Masaki Imanishi, Keisuke Ishizawa, Takumi Sakurada, Yuki Ishizawa, Noriko Yamano, Yoshitaka Kihira, Yasumasa Ikeda, Koichiro Tsuchiya, Toshiaki Tamaki
  • Journal Title: Yakugaku Zasshi Volume: 134 Pages: 715-719
  • NAID: 130004427995
  • Peer Reviewed / Open Access
• [Journal Article] Bovine milk-derived lactoferrin exerts proangiogenic effects in an Src-Akt-eNOS-dependent manner in response to ischemia. (2013)
  • Author(s): Ikeda Yasumasa, et al
  • Journal Title: J Cardiovasc Pharmacol Volume: 未定 Issue: 5 Pages: 423-429
  • DOI: 10.1097/fjc.0b013e318287d526
  • Peer Reviewed
• [Journal Article] A novel prodrug strategy for extremely hydrophobic agents: Conjugation to symmetrically branched glycerol trimer improves pharmacological and pharmacokinetic properties of fenofibrate (2013)
  • Author(s): Licht Miyamoto, Masashi Watanabe, Chiaki Taoka, Mai Kono, Yosuke Tomida, Tsuyoshi Matsushita, Masaki Kamiya, Hatsuhiko Hattori, Keisuke Ishizawa, Shinji Abe, Hisao Nemoto, Koichiro Tsuchiya
  • Journal Title: Mol Pharmaceutics Volume: 10 Issue: 7 Pages: 2723-2729
  • DOI: 10.1021/mp400133j
  • Peer Reviewed
• [Presentation] 大動脈解離発症における血管内皮機能障害の関与 (2015)
  • Author(s): 戸谷紘基, 石澤啓介, 石澤有紀, 小原佑介, 長尾朋子, 今西正樹, 木平孝高, 池田康将3, 土屋浩一郎, 玉置俊晃
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] 新規薬剤誘発性大動脈解離モデルを用いたスタチンの効果の検討 (2014)
  • Author(s): 石澤 有紀, 石澤 啓介, 長尾 朋子, 戸谷 紘基, 小原 佑介, 細岡 真由子, 高田 真衣, 木平 孝高, 池田 康将, 土屋 浩一郎, 玉置 俊晃
  • Organizer: 第24回循環薬理学会
  • Place of Presentation: 山形テルサ（山形県・山形市）
  • Year and Date: 2014-12-05
• [Presentation] Nitrosonifedipine ameliorates the progression of aortic aneurysms by exerting antioxidative effects (2014)
  • Author(s): Keisuke Ishizawa, Yusuke Kohara, Tamkumi Sakurada, Hiroki Toya, Yutaka Iki, Yuki Izawa-Ishizawa, Yoshitaka Kihira, Yasumasa Ikeda, Koichiro Tsuchiya, Toshiaki Tamaki
  • Organizer: European Society of Cardiology Congress 2014
  • Place of Presentation: Barcelona (Spain)
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] 血管内皮障害を介する新規大動脈解離モデルの作製 (2014)
  • Author(s): 戸谷紘基、石澤啓介、小原佑介、長尾朋子、石澤有紀、木平孝高、池田康将、土屋浩一郎、玉置俊晃
  • Organizer: 次世代を担う創薬・医療薬理シンポジウム2014
  • Place of Presentation: 近畿大学 東大阪キャンパス（大阪府・東大阪市）
  • Year and Date: 2014-08-30
• [Presentation] 薬剤誘導性大動脈瘤モデルに対するニトロソニフェジピンの効果 (2014)
  • Author(s): 小原佑介、石澤啓介、櫻田巧、戸谷紘基、長尾朋子、壱岐豊、石澤有紀、木平孝高、池田康将、土屋浩一郎、玉置俊晃
  • Organizer: 第125回日本薬理学会近畿部会
  • Place of Presentation: 岡山コンベンションセンター（岡山県・岡山市）
  • Year and Date: 2014-06-20
• [Presentation] 血管リモデリングにおける低酸素誘導因子HIF-1αの役割 (2014)
  • Author(s): 今西正樹、冨田修平、石澤啓介、木平孝高、石澤有紀、池田康将、 山野範子、土屋浩一郎、玉置俊晃
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本大学（熊本県）
• [Presentation] Nitrosonifedipine prevents the progression of diabetic nephropathy via attenuating the expression of intrarenal angiotensinogen and oxidative stress (2013)
  • Author(s): Keisuke Ishizawa, Noriko Yamano, Hiroyuki Kobori, Maki Urushihara, Yuki Izawa-Ishizawa, Yoshitaka Kihira, Yasumasa Ikeda, Koichiro Tsuchiya, Toshiaki Tamaki
  • Organizer: High Blood Pressure Research 2013 Scientific Sessions
  • Place of Presentation: New Orleans Marriott（アメリカ）
• [Presentation] 脂肪細胞の低酸素誘導因子欠損による耐糖能改善メカニズムの解析 (2013)
  • Author(s): 三宅真理子、木平孝高、冨田修平、山野範子、石澤有紀、石澤啓介、池田康将、土屋浩一郎、玉置俊晃
  • Organizer: 第52回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
  • Place of Presentation: 松山大学（愛媛県）
• [Presentation] 血管傷害モデルに伴う血管リモデリングにおける骨髄由来細胞の HIF1αの役割 (2013)
  • Author(s): 村上正樹、前田悠作、冨田修平、今西正樹、木平孝高、石澤啓介、山野範子、石澤有紀、池田康将、土屋浩一郎、玉置俊晃
  • Organizer: 第52回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
  • Place of Presentation: 松山大学（愛媛県）
• [Presentation] 平滑筋由来 HIF-1 αがアンジオテンシン II 誘発血管リモデリングに関与するメカニズム (2013)
  • Author(s): 鈴木雄太、今西正樹、冨田修平、石澤啓介、木平孝高、池田康将、山野範子、石澤有紀、土屋浩一郎、玉置俊晃
  • Organizer: 第52回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
  • Place of Presentation: 松山大学（愛媛県）
• [Presentation] 血管傷害モデルに伴う血管リモデリング形成過程には、傷害部位に動員される骨髄由来細胞のHIFが関与する
  • Author(s): 村上正樹、冨田修平、前田悠作、今西正樹、山野範子、石澤有紀、木平孝高、石澤啓介、池田康将、土屋浩一郎、玉置俊晃
  • Organizer: 次世代を担う創薬・医療薬理シンポジウム2013
  • Place of Presentation: 熊本大学（熊本県）
• [Presentation] 肥満に伴う脂肪組織炎症に対する低酸素誘導因子の役割
  • Author(s): 木平孝高、冨田修平、山野範子、石澤有紀、石澤啓介、池田康将、土屋浩一郎、玉置俊晃
  • Organizer: 第124回日本薬理学会近畿部会
  • Place of Presentation: 京都ガーデンパレス(京都府)
• [Presentation] 薬剤誘導性大動脈瘤モデルにおける平滑筋由来hypoxia-inducible factor-1αの役割
  • Author(s): 今西正樹、冨田修平、黒部裕嗣、石澤啓介、木平孝高、池田康将、山野範子、石澤有紀、土屋浩一郎、玉置俊晃
  • Organizer: 第23回日本循環薬理学会
  • Place of Presentation: 福岡大学（福岡県）