title: Pdcd4 deficiency enhances macrophage lipoautophagy and attenuates foam cell formation and atherosclerosis in mice.
abstract: Macrophage foam cells, a major component of the atherosclerotic lesion, have vital roles in the development of atherosclerosis. Lipoautophagy, a type of autophagy characterized by selective delivery of lipid droplet for lysosomal degradation, may impact atherosclerosis by regulating macrophage foam cell formation. Previously, we reported that programmed cell death 4 (PDCD4), a tumor suppressor, negatively regulated autophagy in tumor cells. However, its roles in macrophage lipoautophagy, foam cell formation and atherosclerosis remain to be established. Here we found that Pdcd4 deficiency clearly improved oxidized low-density lipoproteins-impaired autophagy efflux, promoted autophagy-mediated lipid breakdown in murine macrophages and thus prevented macrophage conversion into foam cells. Importantly, Pdcd4 deficiency in mice significantly upregulated macrophage autophagy in local plaques along with attenuated lipid accumulation and atherosclerotic lesions in high-fat-fed Apolipoprotein E knockout mice. Bone marrow transplantation experiment demonstrated that PDCD4-mediated autophagy in hematopoietic cells contributed to the development of atherosclerosis. These results indicate that endogenous PDCD4 promotes for macrophage foam cell formation and atherosclerosis development via inhibiting autophagy and provides new insights into atherogenesis, suggesting that promoting macrophage autophagy through downregulating PDCD4 expression may be beneficial for treating atherosclerosis.
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, China.|Department of Hematology, the Second Hospital of Shandong University, Jinan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, China.|Basic Research Center, Shandong Cancer Hospital, Jinan, China.
authors.forename: X
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, China.
authors.forename: C
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, China.
authors.forename: F
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: F
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Y H
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism; D001343:Autophagy; D005487:Foam Cells / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C498443:Pdcd4 protein, mouse; D016601:RNA-Binding Proteins