4-phenylbutyrate and valproate treatment attenuates the progression of atherosclerosis and stabilizes existing plaques
4-phenylbutyrate and valproate treatment attenuates the progression of atherosclerosis and stabilizes existing plaques
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DOI：
10.1016/j.atherosclerosis.2017.09.034
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发表时间：
2017-11-01
期刊：
影响因子：
5.3
通讯作者：
Werstuck, Geoff H.
中科院分区：
文献类型：
--
作者：
Huang, Aric;Young, Tayler L.;Werstuck, Geoff H.
背景和目标：最近的证据表明，通过糖原合成酶激酶（GSK）-3 α/β的内质网（ER）应激信号参与了促动脉粥样硬化过程的激活。在这项研究中，我们在小鼠模型中检测了干扰ER应激-GSK 3 α/β信号传导的小分子对动脉粥样硬化进展和消退的影响。方法：为了检测动脉粥样硬化的进展，低密度脂蛋白受体缺陷将Ldlr（-/-）小鼠置于高脂饮食（HFD）中，并用化学伴侣4-苯基丁酸酯（4-phenylbutyrate）处理。（4PBA，3.8 g/L饮用水）或GSK 3 α/β抑制剂丙戊酸盐（VPA，625 mg VPA/kg饲料），持续10周。为了检查对动脉粥样硬化消退的潜在影响，将4周龄Ldlr（-/-）小鼠置于HFD上16周。小鼠亚组在这个时候收获或切换到一个食物（低脂肪）的饮食，或食物饮食与4PBA或VPA治疗4 weeks.Results：在进展模型中，4PBA和VPA治疗的小鼠有显着减少病变和坏死的核心大小。治疗对代谢参数没有影响，包括血浆和肝脏脂质水平或斑块组成。在回归模型中，4PBA或VPA治疗的小鼠显示病变大小无变化，但病变具有显著更小的坏死核心，血管平滑肌细胞含量增加，胶原蛋白含量增加。这些功能是一致的更稳定plaics.Conclusions：药理衰减的ER应力或抑制GSK 3 α/β阻碍发展的动脉粥样硬化Ldlr（-/-）小鼠，并出现促进稳定现有的病变。(C)2017爱思唯尔B. V.保留所有权利。
Background and aims: Recent evidence suggests that endoplasmic reticulum (ER) stress signaling through glycogen synthase kinase (GSK)-3 alpha/beta is involved in the activation of pro-atherosclerotic processes. In this study, we examined the effects of small molecules that interfere with ER stress-GSK3 alpha/beta signaling on the progression and regression of atherosclerosis in a mouse model.Methods: To examine atherosclerotic progression, low-density lipoprotein receptor deficient (Ldlr(-/-)) mice were placed on a high-fat diet (HFD) and treated with the chemical chaperone, 4-phenylbutyrate (4PBA, 3.8 g/L drinking water), or the GSK3 alpha/beta inhibitor, valproate (VPA, 625 mg VPA/kg diet), for 10 weeks. To examine potential effects on atherosclerotic regression, 4 week old Ldlr(-/-) mice were placed on a HFD for 16 weeks. Subsets of mice were harvested at this time or switched to a chow (low fat) diet, or a chow diet with 4PBA or VPA treatment for 4 weeks.Results: In the progression model, the 4PBA-and VPA-treated mice had significantly reduced lesion and necrotic core size. Treatments had no effect on metabolic parameters, including plasma and hepatic lipid levels, or plaque composition. In the regression model, mice with 4PBA or VPA treatment showed no alterations in lesion size, but the lesions had significantly smaller necrotic cores, increased vascular smooth muscle cell content, and increased collagen content. These features are consistent with more stable plaques.Conclusions: The pharmacological attenuation of ER stress or inhibition of GSK3 alpha/beta impedes the development of atherosclerosis in Ldlr(-/-) mice and appears to promote the stabilization of existing lesions. (C) 2017 Elsevier B.V. All rights reserved.