Valproate Attenuates Accelerated Atherosclerosis in Hyperglycemic ApoE-Deficient Mice
Valproate Attenuates Accelerated Atherosclerosis in Hyperglycemic ApoE-Deficient Mice
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DOI：
10.2353/ajpath.2009.080385
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发表时间：
2009-01-01
影响因子：
6
通讯作者：
Werstuck, Geoff H.
中科院分区：
文献类型：
--
作者：
Bowes, Anna J.;Khan, Mohammad I.;Werstuck, Geoff H.
我们先前已经证明，葡萄糖胺促进血管细胞内质网（ER）应激，导致炎症和脂质积聚-动脉粥样硬化的标志性特征。用糖原合成酶激酶（GSK）-3抑制剂预处理可保护培养的细胞免受ER应激诱导的功能障碍。在此，我们评估GSK-3在高血糖和ER应激的促动脉粥样硬化作用中的潜在作用。我们发现，GSK-3缺陷的小鼠胚胎成纤维细胞不积累未酯化的胆固醇ER应激条件下。此外，GSK-3抑制剂（包括丙戊酸盐）可减弱野生型小鼠胚胎成纤维细胞中ER应激诱导的未酯化胆固醇蓄积。在体内，我们发现高血糖apoE基因缺陷小鼠与血糖正常对照小鼠相比，加速了主动脉根部的动脉粥样硬化形成。相对于未补充的对照组，喂食625 mg/kg丙戊酸盐饲料的小鼠的病变体积显著减小。丙戊酸盐补充对血糖或血脂的血浆水平或病变中ER应激诊断标志物的表达无明显影响。在喂食丙戊酸盐饲料的小鼠中观察到总肝脂质（>50.4%）和肝脏GSK-3 β活性（> 55.8%）显著降低。总之，在高血糖apoE缺陷小鼠中，低水平丙戊酸盐饮食补充可显著减弱动脉粥样硬化形成。丙戊酸盐的体内抗动脉粥样硬化作用与其体外抑制GSK-3和干扰促动脉粥样硬化ER应激信号通路的能力一致。(Am J Pathol 2009，174：330-342; DOI：10.2353/ajpath.2009.080385）
We have previously shown that glucosamine promotes endoplasmic reticulum (ER) stress in vascular cells leading to both inflammation and lipid accumulation-the hallmark features of atherosclerosis. Pretreatment with glycogen synthase kinase (GSK)-3 inhibitors protects cultured cells from ER stress-induced dysfunction. Here we evaluate the potential role of GSK-3 on the pro-atherogenic effects of hyperglycemia and ER stress. We show that GSK-3-deficient mouse embryonic fibroblasts do not accumulate unesterified cholesterol under conditions of ER stress. Furthermore, GSK-3 inhibitors, including valproate, attenuate ER stress-induced unesterified cholesterol accumulation in wild-type mouse embryonic fibroblasts. In vivo we show that hyperglycemic apoE-deficient mice have accelerated atherogenesis at the aortic root compared with normoglycemic control mice. Mice fed a diet supplemented with 625 mg/kg valproate have significantly reduced lesion volume relative to nonsupplemented controls. Valproate supplementation has no apparent effect on the plasma levels of either glucose or lipids or on the expression of diagnostic markers of ER stress in the lesion. Significant reductions were observed in total hepatic lipids (>50.4%) and hepatic GSK-3 beta activity (> 55.8%) in mice fed the valproate diet. In conclusion, dietary supplementation with low levels of valproate significantly attenuates atherogenesis in hyperglycemic apoE-deficient mice. The in vivo anti-atherogenic effects of valproate are consistent with its ability to inhibit GSK-3 and interfere with pro-atherogenic ER stress signaling pathways in vitro. (Am J Pathol 2009, 174:330-342; DOI: 10.2353/ajpath.2009.080385)