Skeletal muscle-specific forkhead box protein-O1 overexpression suppresses atherosclerosis progression in apolipoprotein E-knockout mice
Skeletal muscle-specific forkhead box protein-O1 overexpression suppresses atherosclerosis progression in apolipoprotein E-knockout mice
复制标题
骨骼肌特异性叉头盒蛋白-O1过表达抑制载脂蛋白E敲除小鼠的动脉粥样硬化进展
DOI：
10.1016/j.bbrc.2021.01.001
复制
发表时间：
2021
影响因子：
3.1
通讯作者：
Miura Shinji
中科院分区：
文献类型：
--
作者：
Shimba Yuki;Senda Rena;Katayama Keigo;Morita Akihito;Ikeda Masahiko;Kamei Yasutomi;Miura Shinji
据报道，热量限制（CR）可预防动脉粥样硬化疾病。此外，CR诱导骨骼肌中的叉头盒蛋白-O 1（FOXO-1）表达，改变骨骼肌的特征。我们之前报道过，在动脉粥样硬化载脂蛋白E基因敲除（ApoE-KO）小鼠模型中，由过氧化物酶体增殖物激活受体γ共激活因子-1 α过表达诱导的骨骼肌特征变化可抑制动脉粥样硬化进展。因此，我们假设FOXO-1诱导的骨骼肌交替也可能在ApoE-KO小鼠中具有抗动脉粥样硬化作用。在这项研究中，我们研究了骨骼肌特异性FOXO-1过表达是否抑制ApoE-KO小鼠动脉粥样硬化的进展。我们产生了ApoE-KO/FOXO-1小鼠，其中ApoE-KO小鼠与呈现骨骼肌特异性FOXO-1过表达（FOXO-1 Tg）的小鼠杂交。在20周龄时处死小鼠，测量动脉粥样硬化斑块面积和斑块中的蛋白表达。此外，我们使用从FOXO-1 Tg小鼠收集的血清测量了肿瘤坏死因子α（TNFα）诱导的人脐静脉内皮细胞（HUVEC）中的mRNA表达。因此，与ApoE-KO小鼠相比，ApoE-KO/FOXO-1小鼠显示动脉粥样硬化斑块面积减少65%，同时血管细胞粘附分子-1（VCAM-1）和巨噬细胞浸润减少。与野生型小鼠血清相比，从FOXO-1 Tg小鼠收集的血清显著抑制TNFα处理的HUVEC中VCAM-1（动脉粥样硬化起始因子）的mRNA表达。因此，这些数据表明骨骼肌特异性FOXO-1过表达抑制ApoE-KO小鼠动脉粥样硬化的进展。在某种程度上，CR诱导的抗动脉粥样硬化作用可归因于骨骼肌中的FOXO-1上调。
Calorie restriction (CR) reportedly prevents atherosclerotic diseases. Furthermore, CR induces forkhead box protein-O1 (FOXO-1) expression in the skeletal muscle, altering the character of the skeletal muscle. We previously reported that the change in skeletal muscle character, induced by the overexpression of peroxisome proliferator-activated receptor γ coactivator-1α, suppresses atherosclerotic progression in an atherosclerotic apolipoprotein E-knockout (ApoE-KO) mouse model. Thus, we hypothesized that skeletal muscle alternation induced by FOXO-1 may also have an anti-atherosclerotic effect in ApoE-KO mice. In this study, we investigated whether skeletal muscle-specific FOXO-1 overexpression suppresses the progression of atherosclerosis in ApoE-KO mice. We generated ApoE-KO/FOXO-1 mice, in which an ApoE-KO mouse was crossbred with a mouse presenting skeletal muscle-specific FOXO-1 overexpression (FOXO-1Tg). The mice were sacrificed at 20 weeks of age, and atherosclerotic plaque area and protein expression in the plaque were measured. Additionally, we measured the tumor necrosis factor α (TNFα)- induced mRNA expression in human umbilical vein endothelial cells (HUVECs), using serum collected from the FOXO-1Tg mice. Accordingly, ApoE-KO/FOXO-1 mice showed a 65% reduced atherosclerotic plaque area when compared with the ApoE-KO mice, with concomitantly reduced vascular cell adhesion molecule-1 (VCAM-1) and macrophage infiltration. As compared to serum from wild-type mice, the serum collected from the FOXO-1Tg mice significantly suppressed the mRNA expression ofVCAM-1, an atherosclerosis initiation factor, in TNFα-treated HUVECs. Therefore, these data suggest that skeletal muscle-specific FOXO-1 overexpression suppresses the progression of atherosclerosis in ApoE-KO mice. In part, the CR-induced anti-atherosclerotic effect could be attributed to FOXO-1 upregulation in the skeletal muscle.