title: Systemic application of 3-methyladenine markedly inhibited atherosclerotic lesion in ApoE-/-mice by modulating autophagy, foam cell formation and immune-negative molecules.
abstract: A growing body of evidence demonstrates that autophagy, an evolutionarily conserved intracellular degradation process, is involved in the pathogenesis of atherosclerosis and has become a potential therapeutic target. Here we tested the effect of two inhibitors of phosphatidylinositol 3-kinase, 3-methyladenine (3-MA) and 2-(4-morpholinyl)-8-phenyl-chromone (LY294002), commonly used as inhibitors of autophagy, in atherosclerosis in apolipoprotein E-/-mice. Systemic application of 3-MA but not LY294002 markedly reduced the size of atherosclerotic plaque and increased the stability of lesions in high-fat diet-fed mice as compared with controls. Furthermore, 3-MA had multiple atheroprotective effects, including modulating macrophage autophagy and foam cell formation and altering the immune microenvironment. Long-term treatment with 3-MA promoted oxidized low-density lipoprotein (oxLDL)-induced macrophage autophagy and suppressed foam cell formation and cell viability in vitro. Furthermore, systemic application of 3-MA promoted lipid droplet breakdown and decreased apoptosis, most likely associated with autophagy. 3-MA treatment strikingly enhanced the expression of immune-negative molecules such as interleukin 10 (IL-10), transforming growth factor β and IL-35, as well as forkhead box P3 (Foxp3), the specific transcriptional factor for regulatory T cells, but did not affect the level of proinflammatory cytokines in the arterial wall. We provide strong evidence for the potential therapeutic benefit of 3-MA in inhibiting atherosclerosis development and improving plaque stability.
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan 250012, Shandong, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Dai
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan 250012, Shandong, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan 250012, Shandong, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan 250012, Shandong, China.
authors.forename: Liyang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan 250012, Shandong, China.
authors.forename: Xingguo
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan 250012, Shandong, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan 250012, Shandong, China.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neuroscience, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Fengming
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan 250012, Shandong, China.
authors.forename: Faliang
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan 250012, Shandong, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan 250012, Shandong, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan 250012, Shandong, China.
authors.forename: Yongyu
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan 250012, Shandong, China.
authors.forename: Jianing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan 250012, Shandong, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan 250012, Shandong, China.
authors.forename: Lining
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology*; D001343:Autophagy / Q000187:drug effects*; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D060833:Cellular Microenvironment / Q000187:drug effects; D059305:Diet, High-Fat; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D066292:Lipid Droplets / Q000187:drug effects / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; C025946:3-methyladenine; D000225:Adenine