Analysis of the mechanisms for antiatherogenic effect of bone marrow AT2 receptor by using gene-targeted mice

• Project/Area Number: 17590760
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: YAMADA Hiroyuki Kyoto Prefectural University of Medicine, Graduate School of Medicine, Assistant Professor, 医学研究科, 助教 (00240036)
• Co-Investigator(Kenkyū-buntansha): MATSUBARA Hiroaki Kyoto Prefectural University of Medicine, Graduate School of Medicine, Professor, 医学研究科, 教授 (10239072)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2005: ¥2,400,000 (Direct Cost: ¥2,400,000)
• Keywords: angiotensin II / atherosclerosis / bone marrow cells / progenitors / receptors / アンジオテンシン

Research Abstract

Objective : The angiotensin II (Ang II) type 1 (AT_1) and type 2 (AT_2) receptor play a key roles in atherogenesis ; however, bone marrow (BM) AT_1 and AT_2-mediated actions remain undefined. The purpose of this study was to elucidate the effect of BM-AT_1 and BM-AT_2 on the pathogenesis of atherosclerosis development and vascular repair.
Methods and Results : (1) Atherosclerosis model ; ApoE-KO mice reconstituted with Agtrl^<-/->marrow (apoE-KO/BM-Agtrl^<-/->) showed a significant reduction in atherosclerotic lesions compared with apoE-KO/BM-Agtrl^<+/+> mice. The accumulation of monocytes/macrophages was attenuated in apoE-KO/BM-Agtrl^<-/->mice, concomitant with a decrease in the number of circulating Ly-6C^<hi> monocytes. Flow cytometric analysis of BM cells showed that the number of granulocyte/macrophage progenitors was much lower in apoE-KO/BM-Agtrl^<-/->mice, whereas the number of hematopoietic stem cells (HSCs) did not differ between the two groups, suggesting that BM-AT_1 promot es the transition from HSCs to macrophage progenitors. (2) Vascular repair model ; Total BM cells from Agtr1^<-/->, Agtr2^<-/->, or WT mice were transplanted into BM-ablated WT and femoral arterial injury was performed. Neointimal formation was markedly increased in BM-Agtr2^<-/->compared with BM-WT mice, whereas it was much lower in BM-Agtrl^<-/->mice. Circulating potential vascular progenitor cells, defined by c-kit-/lin-/Sca-1^+ markers, were markedly decreased in BM-Agtrl^<-/->mice, whereas CXR4^+ vascular progenitor cells markedly increased in BM-Agtr2^<-/->mice.
Conclusions : BM-AT_1 is closely implicated in the development of HSCs into macrophage progenitors and vascular progenitors, whereas BM-AT_2 is likely to modulate the property of monocyte/macrophage and vascular progenitors leading to the augmented mobilization from the bone marrow and accumulation at the site of vascular repair. Our study indicates that BM-AT_1 and BM-AT_2 could be a promising therapeutic target for the prevention of cardiovascular events.

Research Products

• [Journal Article] Erythropoietin-mobilized endotherial progenitors enhance reendothelialization via Akt-endothelial nitric oxide synthase activation and prevent neointimal hyperplasia (2006)
  • Author(s): Urao N, Okigaki M, Yamada H, et al.
  • Journal Title: Circulation Research 98 Pages: 1405-1413
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 動脈硬化形成におけるRASの意義 (2006)
  • Author(s): 松原弘明, 山田浩之, 椿本恵則, 横井宏和
  • Journal Title: 日本内科学会雑誌 95 (9) Pages: 138-144
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] アンジオテンシン受容体の分類とその機能 (2006)
  • Author(s): 山田浩之, 椿本恵則, 横井宏和, 松井朗裕, 松原弘明
  • Journal Title: 治療学 40(1) Pages: 21-25
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 血管内皮保護効果 (2006)
  • Author(s): 山田浩之, 松井朗裕, 椿本恵則, 横井宏和, 松原弘明
  • Journal Title: 高血圧(第3版) 64 (5) Pages: 482-486
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Erythropoietin-Mobilized Endothelia Progenitors Enhance Reendothelialization via Akt-Endothelial Nitric Oxide Synthase Activation and Prevent Neointimal Hyperplasia. (2006)
  • Author(s): Urao N, Okigaki M, Yamada H, Adachi Y, Matsuno K, Matsui A, Matsunaga S, Tateishi K, Nomura T, Takahashi T, Tatsumi T, Matsubara H.
  • Journal Title: Cir Res 98 Pages: 1405-1413
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The significance of renin-angiotensin system in the development of atherosclerosis. (2006)
  • Author(s): Matsubara H, Yamada H, Tsubakimoto Y, Yokoi H.
  • Journal Title: Internationl Medicine 95 Pages: 138-144
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Classification of angiotensin receptors and their function (2006)
  • Author(s): Yamada H, Tsubakimoto Y, Yokoi H, Matsui Y, Matsubara H.
  • Journal Title: Biomedicine ＆ Therapeutics 40 Pages: 21-25
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Protective effects on vascular endothelium. (2006)
  • Author(s): Yamada H, Matsui H, Tsubakimoto Y, Yokoi H, Matsubara H.
  • Journal Title: Hypertension 64 Pages: 482-486
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Pharmacological effect of ARB, Improvement of cardiac remodeling. (2006)
  • Author(s): Yamada H, Takata H, Katsume A, Tsubakimoto Y, Yokoi H, Matsubara H.
  • Journal Title: THE ARB Pages: 283-289
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 動脈硬化形成におけるRASの意義 (2006)
  • Author(s): 松原弘明, 山田浩之, 椿本恵則, 横井宏和
  • Journal Title: 日本内科学会雑誌 95(9) Pages: 138-144
• [Journal Article] アンジオテンシン受容体の分類とその機能 (2006)
  • Author(s): 山田浩之, 椿本恵則, 横井宏和, 松井朗裕
  • Journal Title: 治療学 40(1) Pages: 21-25
• [Journal Article] 血管内皮保護効果 (2006)
  • Author(s): 山田浩之, 松井朗裕, 椿本恵則, 横井宏和, 松原弘明
  • Journal Title: 高血圧(第3版) 64(Suppl5) Pages: 482-486
• [Journal Article] Nox1 is involved in angiotensin II-mediated hypertension : A study in Nox1-deficient mice (2005)
  • Author(s): Matsuno K, Yamada H, et al.
  • Journal Title: Circulation 112 Pages: 2677-2685
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] ACE阻害薬とARBの使い分け (2005)
  • Author(s): 山田浩之, 椿本恵則, 横井宏和, 浦尾紀文, 松原弘明
  • Journal Title: Heart View 9(8) Pages: 89-95
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] レニン-アンジオテンシン系と血管新生 (2005)
  • Author(s): 山田浩之, 浦尾紀文, 高宮充孝, 入江秀和, 松原弘明
  • Journal Title: 臨床分子分泌学 (2) 63 (3) Pages: 102-106
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Noxl Is Involved in Angiotensin II-Mediated Hypertension-A Study in Noxl-Deficient Mice. (2005)
  • Author(s): Matsuno K, Yamada H, Iwata K, Jin D, Katsuyama M, Matsuki M, Takai S, Yamanishi K, Miyazaki M, Matsubara H, Yabe-Nishimura C.
  • Journal Title: Circulation 112 Pages: 2677-2685
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The proper use of ACE inhibitor and angiotensin receptor blockade (2005)
  • Author(s): Yamada H, Tsubakimoto Y, Yokoi H, Urao N, Matsubara H.
  • Journal Title: Heart View 9 Pages: 89-95
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Renin-angiotensin system and angiogenesis. (2005)
  • Author(s): Yamada H, Urao N, Takamiya M, Irie H, Matsubara H.
  • Journal Title: Clinical ＆ Molecular Endocrinology (2) 63 Pages: 102-106
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] THE ARB (2006)
  • Author(s): 山田浩之, 高田博輝, 勝目あさ子, 椿本恵則, 横井宏和, 松原弘明
  • Total Pages: 487
  • Publisher: ARBの薬理作用 心臓リモデリング改善作用
  • Description: 「研究成果報告書概要(和文)」より