Laboratory of Nutritional Biochemistry, Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga Ward, Shizuoka City, Shizuoka, 422-8526, Japan; Research Fellow of Japan Society for the Promotion of Science, 5-3-1 Kojimachi, Chiyoda Ward, Tokyo, 102-0083, Japan.
Laboratory of Nutritional Biochemistry, Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga Ward, Shizuoka City, Shizuoka, 422-8526, Japan.
Biochem Biophys Res Commun. 2021 Feb 12;540:61-66. doi: 10.1016/j.bbrc.2021.01.001. Epub 2021 Jan 12.
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 of VCAM-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.
热量限制（CR）据称可预防动脉粥样硬化疾病。此外，CR 会诱导骨骼肌中叉头框蛋白-O1（FOXO-1）的表达，从而改变骨骼肌的特性。我们之前曾报道，过表达过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）引起的骨骼肌特性变化可抑制动脉粥样硬化载脂蛋白 E 敲除（ApoE-KO）小鼠模型中的动脉粥样硬化进展。因此，我们假设 FOXO-1 引起的骨骼肌改变也可能在 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 过表达是否可抑制 ApoE-KO 小鼠的动脉粥样硬化进展。我们生成了 ApoE-KO/FOXO-1 小鼠，其中 ApoE-KO 小鼠与骨骼肌特异性 FOXO-1 过表达（FOXO-1Tg）的小鼠杂交。在 20 周龄时处死小鼠，并测量斑块面积和斑块中的蛋白表达。此外，我们使用从 FOXO-1Tg 小鼠收集的血清，测量人脐静脉内皮细胞（HUVEC）中肿瘤坏死因子α（TNFα）诱导的 mRNA 表达。因此，与 ApoE-KO 小鼠相比，ApoE-KO/FOXO-1 小鼠的动脉粥样硬化斑块面积减少了 65％，同时血管细胞黏附分子-1（VCAM-1）和巨噬细胞浸润减少。与野生型小鼠的血清相比，FOXO-1Tg 小鼠的血清可显著抑制 TNFα处理的 HUVEC 中动脉粥样硬化起始因子 VCAM-1 的 mRNA 表达。因此，这些数据表明骨骼肌特异性 FOXO-1 过表达可抑制 ApoE-KO 小鼠的动脉粥样硬化进展。在某种程度上，CR 诱导的抗动脉粥样硬化作用可能归因于骨骼肌中 FOXO-1 的上调。
