title: Apigenin Attenuates Atherogenesis through Inducing Macrophage Apoptosis via Inhibition of AKT Ser473 Phosphorylation and Downregulation of Plasminogen Activator Inhibitor-2.
abstract: Macrophage survival is believed to be a contributing factor in the development of early atherosclerotic lesions. Dysregulated apoptosis of macrophages is involved in the inflammatory process of atherogenesis. Apigenin is a flavonoid that possesses various clinically relevant properties such as anti-inflammatory, antiplatelet, and antitumor activities. Here we showed that apigenin attenuated atherogenesis in apoE (-/-) mice in an in vivo test. In vitro experiments suggested that apigenin induced apoptosis of oxidized low density lipoprotein- (OxLDL-) loaded murine peritoneal macrophages (MPMs). Proteomic analysis showed that apigenin reduced the expression of plasminogen activator inhibitor 2 (PAI-2). PAI-2 has antiapoptotic effects in OxLDL-loaded MPMs. Enhancing PAI-2 expression significantly reduced the proapoptosis effects of apigenin. Molecular docking assay with AutoDock software predicted that residue Ser473 of Akt1 is a potential binding site for apigenin. Lentiviral-mediated overexpression of Akt1 wild type weakened the proapoptosis effect of apigenin in OxLDL-loaded MPMs. Collectively, apigenin executes its anti-atherogenic effects through inducing OxLDL-loaded MPMs apoptosis. The proapoptotic effects of apigenin were at least partly attributed to downregulation of PAI-2 through suppressing phosphorylation of AKT at Ser473.
authors.affiliation: Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zeng
authors.affiliation: Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Fan
authors.affiliation: The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Diao
authors.affiliation: Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Tang
authors.affiliation: The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China ; Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Xiu-Qiong
authors.initials: XQ
authors.lastname: Fu
authors.affiliation: The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China ; Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Xue-Gang
authors.initials: XG
authors.lastname: Sun
mesh_terms: D000818:Animals; D047310:Apigenin / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D008077:Lipoproteins, LDL; D017396:Plasminogen Activator Inhibitor 2; D020011:Protective Agents; C099252:oxidized low density lipoprotein; D010768:Phosphoserine; D047310:Apigenin; D051057:Proto-Oncogene Proteins c-akt