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

基因靶向小鼠分析骨髓AT2受体抗动脉粥样硬化作用机制

• 批准号: 17590760
• 负责人: YAMADA Hiroyuki
• 金额: $ 2.3万
• 依托单位: Kyoto Prefectural University of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590760/
• 关键词: angiotensin II; atherosclerosis; bone marrow cells; progenitors; receptors; アンジオテンシン

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 … More 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. Less

目的：血管紧张素Ⅱ（angiotensin Ⅱ，Ang Ⅱ）1型受体（AT_1）和2型受体（AT_2）在动脉粥样硬化形成中起重要作用，但骨髓AT_1和AT_2受体介导的作用尚不清楚。方法和结果：（1）动脉粥样硬化模型：ApoE-KO小鼠（apoE-KO/BM-Ag +^<-/+>）与apoE-KO/BM-Ag +^<+/+>小鼠相比，动脉粥样硬化病变明显减轻。单核细胞/巨噬细胞的积累在apoE-KO/BM-Agglutamine ^&lt;-/-&gt;小鼠中减弱，伴随着循环Ly-6C^单核细胞数量的减少<hi>。骨髓细胞的流式细胞术分析显示，apoE-KO/BM-AgglutinA ^&lt;-/-&gt;小鼠的粒/巨噬细胞祖细胞数量明显减少，而造血干细胞（HSC）数量在两组之间没有差异，这表明BM-AT_1促进了apoE-KO/BM-AgglutinA ^&lt;-/-&gt;小鼠的造血干细胞（HSC）数量的增加，而apoE-KO/BM-AgglutinA ^&lt;-/-&gt;小鼠的造血干细胞（HSC）数量的增加。 ...更多信息 从HSC向巨噬细胞祖细胞的转变。(2)血管修复模型;将来自Agtr 1 ^&lt;-/-&gt;、Agtr 2 ^&lt;-/-&gt;或WT小鼠的总BM细胞移植到BM消融的WT中，并进行股动脉损伤。与BM-WT小鼠相比，BM-Agtr 2 &lt;-/-&gt;小鼠中的新生内膜形成显著增加，而BM-Agtr 2 &lt;-/-&gt;小鼠中的新生内膜形成低得多。在BM-Agtr 2 ^&lt;-/-&gt;小鼠中，由c-kit-/lin-/Sca-1^+标记物定义的循环潜在血管祖细胞显著减少，而CXR 4 ^+血管祖细胞显著增加。BM-AT_1与HSC发育为巨噬细胞祖细胞和血管祖细胞密切相关，而BM-AT_2可能调节单核/巨噬细胞和血管祖细胞的性质，导致从骨髓的动员增加和在血管修复部位的积聚。我们的研究表明，BM-AT_1和BM-AT_2可能是预防心血管事件的一个有希望的治疗靶点。少

项目成果

Classification of angiotensin receptors and their function

血管紧张素受体的分类及其功能

• 发表时间: 2006
• 期刊: Biomedicine ＆ Therapeutics 40
• 作者: Yamada H;Tsubakimoto Y;Yokoi H;Matsui Y;Matsubara H.
• 通讯作者: Matsubara H.

Pharmacological effect of ARB, Improvement of cardiac remodeling.

ARB的药理作用，改善心脏重构。

• 发表时间: 2006
• 期刊: THE ARB
• 作者: Yamada H;Takata H;Katsume A;Tsubakimoto Y;Yokoi H;Matsubara H.
• 通讯作者: Matsubara H.

Renin-angiotensin system and angiogenesis.

肾素-血管紧张素系统和血管生成。

• 发表时间: 2005
• 期刊: Clinical ＆ Molecular Endocrinology (2) 63
• 作者: Yamada H;Urao N;Takamiya M;Irie H;Matsubara H.
• 通讯作者: Matsubara H.

The significance of renin-angiotensin system in the development of atherosclerosis.

肾素-血管紧张素系统在动脉粥样硬化发生发展中的意义。

• 发表时间: 2006
• 期刊: Internationl Medicine 95
• 作者: Matsubara H;Yamada H;Tsubakimoto Y;Yokoi H.
• 通讯作者: Yokoi H.

Noxl Is Involved in Angiotensin II-Mediated Hypertension-A Study in Noxl-Deficient Mice.

Noxl 参与血管紧张素 II 介导的高血压——一项针对 Noxl 缺陷小鼠的研究。

• 发表时间: 2005
• 期刊: Circulation 112
• 作者: Matsuno K;Yamada H;Iwata K;Jin D;Katsuyama M;Matsuki M;Takai S;Yamanishi K;Miyazaki M;Matsubara H;Yabe-Nishimura C.
• 通讯作者: Yabe-Nishimura C.