title: Mitochondrion-Targeted Peptide SS-31 Inhibited Oxidized Low-Density Lipoproteins-Induced Foam Cell Formation through both ROS Scavenging and Inhibition of Cholesterol Influx in RAW264.7 Cells.
abstract: Foam cell formation as a result of imbalance of modified cholesterol influx and efflux by macrophages is a key to the occurrence and development of atherosclerosis. Oxidative stress is thought to be involved in the pathogenesis of atherosclerosis. SS-31 is a member of the Szeto-Schiller (SS) peptides shown to specifically target the inner mitochondrial membrane to scavenge reactive oxygen species. In this study, we investigated whether SS-31 may provide protective effect on macrophage from foam cell formation in RAW264.7 cells. The results showed that SS-31 inhibited oxidized low-density lipoproteins (ox-LDL)-induced foam cell formation and cholesterol accumulation, demonstrated by intracellular oil red O staining and measurement of cholesterol content. The mechanism was revealed that SS-31 did not only significantly attenuated ox-LDL-induced generation of reactive oxygen species (ROS) and increased the activities of superoxide dismutases, but also dose-dependently inhibited the expression of CD36 and LOX-1, two scavenger receptors of ox-LDL, while the expression of ATP-binding cassette A1 and G1, playing a pivotal role in cholesterol efflux, was not affected. As a result, SS-31 decreased pro-inflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha, suggesting the prevention of inflammatory responses. In conclusion, our results demonstrate that SS-31 provides a beneficial effect on macrophages from foam cell formation, likely, through both ROS scavenging and inhibition of cholesterol influx. Therefore, SS-31 may potentially be of therapeutic relevance in prevention of human atherogenesis.
authors.affiliation: Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China. shuangying9088@163.com.
authors.forename: Shuangying
authors.initials: S
authors.lastname: Hao
authors.affiliation: Department of Vascular Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China. jijiajie071@foxmail.com.
authors.forename: Jiajie
authors.initials: J
authors.lastname: Ji
authors.affiliation: Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China. zhting1210@163.com.
authors.forename: Hongting
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China. sjbslc@126.com.
authors.forename: Longcheng
authors.initials: L
authors.lastname: Shang
authors.affiliation: Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China. wujinghappy@126.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China. hhli900217@163.com.
authors.forename: Huihui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Vascular Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China. qiaotongmail@aliyun.com.
authors.forename: Tong
authors.initials: T
authors.lastname: Qiao
authors.affiliation: Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China. likuanyu@nju.edu.cn.
authors.forename: Kuanyu
authors.initials: K
authors.lastname: Li
mesh_terms: D000818:Animals; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D005487:Foam Cells / Q000187:drug effects*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D008077:Lipoproteins, LDL; D009842:Oligopeptides; D017382:Reactive Oxygen Species; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; C099252:oxidized low density lipoprotein; D002784:Cholesterol
keywords: CD36; SS-31; foam cells; inflammation; lipid accumulation; macrophage; oxidative stress