title: Autophagy Induction Protects Against 7-Oxysterol-induced Cell Death via Lysosomal Pathway and Oxidative Stress.
abstract: 7-Oxysterols are major toxic components in oxidized low-density lipoprotein and human atheroma lesions, which cause lysosomal membrane permeabilization (LMP) and cell death. Autophagy may function as a survival mechanism in this process. Here, we investigated whether 7-oxysterols mixed in an atheroma-relevant proportion induce autophagy, whether autophagy induction influences 7-oxysterol-mediated cell death, and the underlying mechanisms, by focusing on cellular lipid levels, oxidative stress, and LMP in 7-oxysterol-treated macrophages. We found that 7-oxysterols induced cellular lipid accumulation, autophagy dysfunction, and cell death in the form of both apoptosis and necrosis. Exposure to 7-oxysterols induced autophagic vacuole synthesis in the form of increased autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and LC3-phosphatidylethanolamine conjugate (LC3-II) and autophagic vacuole formation. This led to an accumulation of p62, indicating a reduction in autophagic vacuole degradation. Importantly, autophagy induction significantly reduced 7-oxysterol-mediated cell death by diminishing LMP and oxidative stress. Moreover, autophagy induction minimized cellular lipid accumulation induced by 7-oxysterols. These findings highlight the importance of autophagy in combating cellular stress, LMP, and cell death in atherosclerosis. Therefore, activation of the autophagy pathway may be a potential therapeutic strategy for prevention of necrotic core formation in atherosclerotic lesions.
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.; Occupational and Environmental Medicine, Heart and Medicine Center, Region Östergötland, Linköping, Sweden.
authors.forename: Xi-Ming
authors.initials: XM
authors.lastname: Yuan
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Nargis
authors.initials: N
authors.lastname: Sultana
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Siraj
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.; Gynecology and Obstetrics, University Hospital, Linköping, Sweden.
authors.forename: Liam J
authors.initials: LJ
authors.lastname: Ward
authors.affiliation: Occupational and Environmental Medicine, Heart and Medicine Center, Region Östergötland, Linköping, Sweden.; Rehabilitation Medicine, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.; Pain and Rehabilitation Center, Anaesthetics, Operations and Specialty Surgery Center, Region Östergötland, Linköping, Sweden.
authors.forename: Bijar
authors.initials: B
authors.lastname: Ghafouri
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.; Gynecology and Obstetrics, University Hospital, Linköping, Sweden.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
keywords: autophagy; lysosomal membrane permeabilization; macrophage cell death; oxidative stress