Tesaglitazar, a dual peroxisome proliferator-activated receptor alpha/gamma agonist, reduces atherosclerosis in female low density lipoprotein receptor deficient mice
Tesaglitazar, a dual peroxisome proliferator-activated receptor alpha/gamma agonist, reduces atherosclerosis in female low density lipoprotein receptor deficient mice
复制标题
DOI：
10.1016/j.atherosclerosis.2006.12.012
复制
发表时间：
2007-11-01
期刊：
影响因子：
5.3
通讯作者：
Chait, Alan
中科院分区：
文献类型：
--
作者：
Chira, Ebele C.;McMillen, Timothy S.;Chait, Alan
目的：参与脂质和葡萄糖稳态的转录因子过氧化物酶体增殖物激活受体（PPAR）α（α）和γ（γ）也对血管细胞发挥调节作用，从而表现出抗炎和抗增殖特性。因此，PPAR 激动剂可能通过代谢作用和对血管壁的直接作用来影响动脉粥样硬化形成。我们测试了双 PPAR-α/γ 激动剂替格列扎 (TZ) 是否会在非糖尿病、易患动脉粥样硬化的小鼠模型中减少动脉粥样硬化，且与血浆脂质的影响无关。方法和结果：低密度脂蛋白受体缺陷 (LDLr-/-) 小鼠喂食由 21% 乳脂和 0.15% 胆固醇组成的西式饮食，含或不含 TZ 0.5 mu mol/kg 饮食，持续 12 周。 TZ 减少了雌性 LDLr-/- 小鼠的动脉粥样硬化，但不影响雄性 LDLr-/- 小鼠，且不影响胆固醇和甘油三酯水平、HDL 与双聚糖的结合或炎症标志物血清淀粉样蛋白 A (SAA) 和血清淀粉样蛋白 P (SAP)。 TZ 还可以减少两种性别的肥胖。结论：TZ 通过脂质独立机制减少雌性 LDLr-/- 小鼠的动脉粥样硬化，可能至少部分是通过对血管的直接作用。这些小鼠的体重变化与双 PPAR 激动剂对人类的影响不同。 (c) 2007 Elsevier Ireland Ltd. 保留所有权利。
Objective: The transcription factors, peroxisome proliferator-activated receptors (PPAR) alpha (alpha) and gamma(gamma), which are involved in lipid and glucose homeostasis, also exert modulatory actions on vascular cells where they exhibit anti-inflammatory and anti-proliferative properties. Hence, PPAR agonists potentially can affect atherogenesis both via metabolic effects and direct effects on the vessel wall. We tested whether the dual PPAR-alpha/gamma agonist, tesaglitazar (TZ), would reduce atherosclerosis in a non-diabetic, atherosclerosis-prone mouse model, independent of effects on plasma lipids.Methods and results: Low-density lipoprotein receptor deficient (LDLr-/-) mice were fed a Western type diet consisting of 21% butterfat and 0.15% cholesterol, with or without TZ 0.5 mu mol/kg of diet, for 12 weeks. TZ reduced atherosclerosis in the female, but not male, LDLr-/-mice without affecting cholesterol and triglyceride levels, HDL binding to biglycan, or the inflammatory markers serum amyloid A (SAA) and serum amyloid P (SAP). TZ also decreased adiposity in both genders.Conclusions: TZ reduced atherosclerosis in the female LDLr-/- mice via lipid-independent mechanisms, probably at least in part by direct actions on the vessels. The body weight changes in these mice are different from the effects of dual PPAR agonists seen in humans. (c) 2007 Elsevier Ireland Ltd. All rights reserved.