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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

1
Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China
2
Department of Vascular Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
*
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Molecules 2015, 20(12), 21287-21297; https://doi.org/10.3390/molecules201219764
Received: 25 September 2015 / Revised: 11 November 2015 / Accepted: 20 November 2015 / Published: 1 December 2015
(This article belongs to the Section Medicinal Chemistry)
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. View Full-Text
Keywords: SS-31; CD36; lipid accumulation; macrophage; foam cells; oxidative stress; inflammation SS-31; CD36; lipid accumulation; macrophage; foam cells; oxidative stress; inflammation
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Hao, S.; Ji, J.; Zhao, H.; Shang, L.; Wu, J.; Li, H.; Qiao, T.; Li, K. 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. Molecules 2015, 20, 21287-21297.

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