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，我们第一次证明了单侧肾切除术引起的动脉粥样硬化发展与PAT特异性AGT mRNA表达和Ang II分泌增加密切相关，而单核细胞/巨噬细胞的募集没有增强。单肾切除apoE^<-/->小鼠在葡萄糖负荷后HOMA-IR指数和血浆胰岛素浓度显著升高，胰岛素刺激分离的PAT成熟脂肪细胞以贮库特异性方式显著增加AGT mRNA表达，这表明胰岛素抵抗相关的高胰岛素血症最可能导致RAS的PAT特异性激活。与此相反，表达的粘附分子在血管和循环炎症单核细胞的数量，这在动脉粥样硬化发展的早期阶段发挥了至关重要的作用，没有改变单肾切除术。此外，在apoE^<-/->/AT 1aR ^<-/->小鼠中或通过血管紧张素II 1型受体阻断剂（奥美沙坦）治疗完全抑制了单侧肾切除术引起的动脉粥样硬化加速发展，进一步支持了RAS的PAT特异性激活实质上参与CKD相关动脉粥样硬化形成的观点，并可能成为预防CKD相关心血管疾病的新治疗靶点。

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

CKDと心血管病

CKD 和心血管疾病

• 发表时间: 2012
• 期刊: Renin Academy Japan Journal
• 作者: 川人浩之;山田浩之;松原弘明
• 通讯作者: 松原弘明

Early inflammatory reactions in atherosclerosis are induced by proline-rich tyrosine kinase/reactive oxygen species-mediated release of tumor necrosis factor- and subsequent activation of the p21Cip1/Ets-1/p300 system.

动脉粥样硬化的早期炎症反应是由富含脯氨酸的酪氨酸激酶/活性氧介导的肿瘤坏死因子的释放以及随后的 p21Cip1/Ets-1/p300 系统的激活诱导的。

• 发表时间: 2011
• 期刊: Arterioscler Thromb Vase Biol
• 作者: 岩井將;堀内正嗣;Katsume A
• 通讯作者: Katsume A

Bone marrow AT2 receptor deficiency aggravates atherosclerosis by augmenting macrophage pro-inflammatory responses

骨髓 AT2 受体缺陷通过增强巨噬细胞促炎症反应而加剧动脉粥样硬化

• 发表时间: 2010
• 作者: Onoue K;Zaima N;Sugiura Y;Isojima T;Okayama S;Horii M;Akai Y;Uemura S;Takemura G;Sakuraba H;Sakaguchi Y;Setou M;Saito Y.;加藤拓
• 通讯作者: 加藤拓

血管周囲脂肪表現型とレニン・アンジオテンシン系慢性腎臓病はRA系賦活化を介して動脈硬化を進展させる

血管周围脂肪表型和肾素-血管紧张素系统慢性肾脏病通过激活 RA 系统导致动脉硬化

• 发表时间: 2010
• 作者: Onoue K;Uemura S;et al;赤池雅史;川人浩之
• 通讯作者: 川人浩之