Identification of a novel gene to promote atherosclerosis development by regulating fatty acid binding protein secreted from dysfunctional kidney

鉴定一种通过调节功能失调的肾脏分泌的脂肪酸结合蛋白来促进动脉粥样硬化发展的新基因

• 批准号: 21590957
• 负责人: YAMADA Hiroyuki
• 金额: $ 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: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21590957/
• 关键词: 血管病態学; 動脈硬化; 慢性腎臓病; 脂肪組織; レニン・アンジオテンシン系; 脂肪酸代謝; 脂肪酸結合蛋白

In this study, we demonstrated for the first time that exaggerated atherosclerosis development elicited by uninephrectomy was closely associated with PAT-specific increases in AGT mRNA expression and Ang II secretion without enhanced recruitment of monocytes/macrophages. HOMA-IR index and plasma insulin concentrations after glucose loading were markedly elevated in uninephrectomized apoE^<-/-> mice, and insulin stimulation of isolated PAT mature adipocytes significantly increased AGT mRNA expression in a depot-specific manner, suggesting that insulin resistance-associated hyperinsulinemia most likely contributed to the PAT-specific activation of RAS. In contrast, expression of adhesion molecules in the vasculature and the number of circulating inflammatory monocytes, which played a crucial role in the early stage of atherosclerosis development, were not altered by uninephrectomy. Moreover, accelerated atherosclerosis development caused by uninephrectomy was completely inhibited in apoE^<-/->/AT1aR^<-/-> mice or by treatment with angiotensin II type 1 receptor blocker(olmesartan), further supporting the notion that PAT-specific activation of RAS is substantially involved in the CKD-associated atherogenesis and could be a novel therapeutic target for the prevention of CKD-associated cardiovascular disease.

在这项研究中，我们首次证明了夸张的动脉粥样硬化发育是由单晶切除术引起的，这与AGT mRNA表达的PAT特异性增加和ANG II分泌的分泌密切相关，而无需增强单核细胞/巨噬细胞的募集。葡萄糖负荷后的HOMA-IR指数和血浆胰岛素浓度在单晶性APOE apoE^< - / - >小鼠中明显升高，以及分离的PAT成熟成熟脂肪细胞的胰岛素刺激显着增加了AGT的AGT mRNA在仓库特异性方式中，这表明胰岛素抵抗 - 抗胰岛素抵抗 - - 相关的高胰岛素血症最有可能导致RAS的PAT特异性激活。相比之下，脉管系统中粘附分子的表达和循环炎性单核细胞的数量在动脉粥样硬化发育的早期发挥了至关重要的作用，并没有通过单态切除术改变。此外，在apoE^< - / - >/at1ar^< - / - >小鼠或用血管紧张素II类型1型受体阻滞剂（Olmesartan）治疗中，完全抑制了由单次切除术引起的加速动脉粥样硬化发展，完全抑制RA的激活基本上与CKD相关的动脉粥样硬化有关，并且可能是预防与CKD相关的心血管疾病的新型治疗靶标。

项目成果

骨髄RASの血管傷害後内膜増生における役割

骨髓RAS在血管损伤后内膜增生中的作用

• 发表时间: 2009
• 期刊: 医学のあゆみ 228(5)
• 作者: 山田浩之;松原弘明
• 通讯作者: 松原弘明

Apoptosis regulator through modulating IAP expression (ARIA) controls the PI3K/Akt pathway in endothelial and endothelial progenitor cells

• DOI: 10.1073/pnas.1101296108
• 发表时间: 2011-06-07
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Koide, Masahiro;Ikeda, Koji;Matsubara, Hiroaki
• 通讯作者: Matsubara, Hiroaki

慢性腎臓病(CKD)における動脈硬化促進の分子メカニズムーアポE欠損マウスCKD腎臓でのマイクロアレイ解析-

慢性肾病 (CKD) 加速动脉硬化的分子机制 - apoE 缺陷小鼠 CKD 肾脏的微阵列分析 -

• 发表时间: 2009
• 作者: 川人浩之;山田浩之;岸田聡;加藤拓;高橋知三郎;沖垣光彦;森泰清;松原弘明
• 通讯作者: 松原弘明

アンジオテンシンII受容体拮抗薬はマクロファージのアポトーシス減少により進展プラーク内の壊死コア形成を抑制する

血管紧张素 II 受体拮抗剂通过减少巨噬细胞凋亡来抑制晚期斑块内坏死核心的形成

• 发表时间: 2010
• 作者: Yamaguchi O;Takeishi Y;et al;岩瀬俊;岸田総
• 通讯作者: 岸田総

Bone marrow angiotensin AT2 receptor deficiency aggravates atherosclerosis by eliminating macrophage liver X receptor-mediated anti-atherogenic actions

骨髓血管紧张素AT2受体缺乏通过消除巨噬细胞肝脏X受体介导的抗动脉粥样硬化作用而加剧动脉粥样硬化

• 发表时间: 2011
• 作者: Kato T;Yamada H;Kawahito H;Irie D;Fukui K;Ikeda K;Okigaki M;Mogi M;Iwai M;Horiuchi M;Matsubara H
• 通讯作者: Matsubara H