Role of LOX-1 and protective effect of PPARγ in the development of atherosclerosis

LOX-1和PPARγ在动脉粥样硬化发展中的作用

• 批准号: 14570641
• 负责人: ANDO Katsuyuki
• 金额: $ 2.24万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570641/
• 关键词: lectin-like oxidized LDL receptor-1 (LOX-1); cytokine; thiazolidinediones; peroxisome proliferator-activated receptor-γ (PPARγ); atherosclerosis; lpr mice; PPARγ knockout mice; tumor necrosis factor-α (TNFα); lprマウス; TNAα; LOX-1; PPARγ; 腎障害

The purpose of this project is to clarify the possible relationship of peroxisome proliferator-activated receptor-γ(PPARγ), which is proposed to inhibit the development and progression of atherosclerosis, and lectin-like oxidized low density lipoprotein (LDL) receptor-i1 (LOX-1), which is considered to play an important role in vascular damage. We demonstrated that PPARγ ligands suppressed LOX-1 overexpression induced by cytokine in bovine aortic endothelial cells (BAEC). Moreover, we elucidated that cytokine (tumor necrosis factor-α TNFα) enaqhnced LOX-1 expression in kidney and aorta of C57/BL6 mice, which was inhibited by thiazolidinediones, a PPARγ ligand. That is, the in-vitro finding was also observed in in-vivo experiment. Then, we evaluated whether LOX-1 expression is upregulated in lpr mice, in which the expression of TNFα is enhanced, as compred to normal mice. However, renal LOX-1 expression was not elevated in lpr mice. The LOX-1 expression might be modified by several autoimmune abnormality. In addition, we used PPARγ knockout heterozygote mice (homozygote mice are viviparously lethal). However, TNFo-induced renal LOX-1 upregulation was not different between PPARγ knockout mice and wild-tupe mice and effect of PPARγ ligand also did not differ. Thus, our results explain pharmacological mechanism of the antiatheroeclerotic action of thiazolidinediones, but do not suggest a role of intrinsic PPARγ, although our data have limitation because the konckout mice were heterozygote.

本研究旨在阐明抑制动脉粥样硬化发生发展的过氧化物酶体增殖物激活受体-γ(PPAR-γ)和被认为在血管损伤中起重要作用的凝集素样氧化型低密度脂蛋白受体-1(LOX-1)之间的可能关系。我们发现PPARγ配体可抑制细胞因子诱导的牛主动脉内皮细胞LOX-1的过度表达。此外，我们还阐明了细胞因子(肿瘤坏死因子-α肿瘤坏死因子α)可促进C57/BL6小鼠肾脏和主动脉LOX-1的表达，这种作用可被γ配体噻唑烷二酮类化合物所抑制。也就是说，体外发现也是在体内实验中观察到的。然后，我们评估了LpR小鼠中LOX-1的表达是否上调，其中肿瘤坏死因子α的表达增强，与正常小鼠相比。然而，在LPR小鼠中，肾脏LOX-1的表达并没有增加。LOX-1的表达可能被几种自身免疫异常所改变。此外，我们还使用了PPARγ基因敲除杂合子小鼠(纯合子小鼠胎生致死)。γ基因敲除小鼠与野生型TUPE小鼠相比，TnFo诱导的肾脏LOX-1表达上调无明显差异，PPARγ配体的作用也无明显差异。因此，我们的结果解释了噻唑烷二酮类化合物抗动脉粥样硬化作用的药理学机制，但并不暗示内在的PPARγ的作用，尽管我们的数据具有局限性，因为基因敲除的小鼠是杂合子。

项目成果

Chiba Y, Ando K, Fujita T: "The protective effects of taurine against renal damage by salt loading in Dahl salt-sensitive rats"Journal of Hypertension. 20. 2269-2274 (2002)

Chiba Y、Ando K、Fujita T：“牛磺酸对 Dahl 盐敏感大鼠中盐负荷引起的肾损伤的保护作用”高血压杂志。

Shimosawa T, Sibagki Y, Ishibashi K, Kitamura K, Kangawa K, Kato S, Ando k, Fujita T: "Adronomedullin, an endogenous peptide, counteracts cardiovascular damage"Circulation. 106. 104-111 (2002)

Shimosawa T、Sibagki Y、Ishibashi K、Kitamura K、Kangawa K、Kato S、Ando k、Fujita T：“Adronomedullin，一种内源性肽，可以抵抗心血管损伤”循环。

Shimosawa T, Ogihara T, Matsui H, Asano T, Ando K, Fujita T.: "Deficiency of adrenomedullin induces insulin resistance by increasing oxidative stress"Hypertension. 41. 1080-1085 (2003)

Shimosawa T、Ogihara T、Matsui H、Asano T、Ando K、Fujita T.：“肾上腺髓质素缺乏通过增加氧化应激诱导胰岛素抵抗”高血压。

Ando K, Fujita T: "Lessons from the adrenomedullin knockout mice"Regulatory Peptide. 112. 85-88 (2003)

Ando K、Fujita T：“肾上腺髓质素敲除小鼠的教训”调节肽。

Ueno T, Kaname S, Takaichi K, Nagase M, Tojo A, Onozato ML, Fujita T: "LOX-1, an oxidized low-density lipoprotein receptor, was upregulated in the kidney of chronic renal failure rats"Hypertension Research. 26. 117-122 (2003)

Ueno T、Kaname S、Takaichi K、Nagase M、Tojo A、Onozato ML、Fujita T：“LOX-1，一种氧化的低密度脂蛋白受体，在慢性肾衰竭大鼠的肾脏中表达上调”高血压研究。