Skeletal muscle-specific forkhead box protein-O1 overexpression suppresses atherosclerosis progression in apolipoprotein E-knockout mice

• Published in: Biochemical and biophysical research communications Vol. 540; pp. 61 - 66
• Main Authors: Shimba, Yuki, Senda, Rena, Katayama, Keigo, Morita, Akihito, Ikeda, Masahiko, Kamei, Yasutomi, Miura, Shinji
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.02.2021
• Subjects: Animals; Apolipoprotein E-knockout mouse; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - pathology; Disease Progression; Forkhead Box Protein O1 - genetics; Forkhead Box Protein O1 - metabolism; Forkhead box protein-O1; Human Umbilical Vein Endothelial Cells; Humans; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal - metabolism; Tumor Necrosis Factor-alpha - metabolism; Vascular cell adhesion molecule-1; Vascular Cell Adhesion Molecule-1 - metabolism; Forkhead box protein-O1; Apolipoprotein E-knockout mouse; Human umbilical vein endothelial cells; Atherosclerosis; Vascular cell adhesion molecule-1
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2021.01.001

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. •Skeletal muscle-specific FOXO-1 overexpression suppressed atherosclerosis.•VCAM-1 and macrophage accumulation were reduced in plaques of ApoE-KO/FOXO-1 mice.•FOXO-1Tg mice-derived serum suppressed TNFα-induced VCAM-1 expression in HUVECs.