title: Endophilin-A2-mediated increase in scavenger receptor expression contributes to macrophage-derived foam cell formation.
abstract: Macrophage-derived foam cell formation (MFCF) is a crucial step in the pathogenesis of atherosclerosis. Uptake of oxidized low-density lipoprotein (oxLDL) by scavenger receptors is indispensable for MFCF. Endophilin-A2 has been reported to regulate clathrin-mediated endocytosis (CME). In this study, we tested the hypothesis that endophilin-A2 regulates oxLDL uptake and MFCF by mediating CME of oxLDL-scavenger receptor complexes.
  
  
  
  In vitro MFCF was induced by oxLDL treatment. Involvement of endophilin-A2 in oxLDL cytomembrane binding, cellular uptake, and MFCF was evaluated by manipulation of endophilin-A2.
  
  
  
  Endophilin-A2 was involved in MFCF via scavenger receptor CD36 and scavenger receptor-A (SR-A)-mediated positive feedback pathways. We observed that oxLDL triggered interaction of endophilin-A2 with CD36 or SR-A, and induced an endophilin-A2-dependent activation of the apoptosis signal-regulating kinase-1 (ASK1)/Jun N-terminal kinase (JNK)/p38 signaling pathway. The activation of ASK1-JNK/p38 signal increased expression of both CD36 and SR-A, which promoted oxLDL cytomembrane binding, cellular uptake, and MFCF. In the absence of oxLDL, endophilin-A2 up-regulated the expression of receptors and Dil-oxLDL binding and uptake, but not the intracellular accumulation of lipids. In the presence of oxLDL, the CME inhibitors pitstop2 and ikarugamycin mimicked the inhibiting effect of endophilin-A2 knockdown and eliminated the elevating effect of endophilin-A2 overexpression on oxLDL uptake and MFCF.
  
  
  
  Endophilin-A2 was identified as a novel molecule regulating MFCF by mechanisms attributable to CME and beyond CME.
authors.affiliation: Cardiac and Cerebral Vascular Research Center, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Er-Wen
authors.initials: EW
authors.lastname: Huang
authors.affiliation: Cardiac and Cerebral Vascular Research Center, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Can-Zhao
authors.initials: CZ
authors.lastname: Liu
authors.affiliation: Cardiac and Cerebral Vascular Research Center, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Si-Jia
authors.initials: SJ
authors.lastname: Liang
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Cardiac and Cerebral Vascular Research Center, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Lv
authors.affiliation: Cardiac and Cerebral Vascular Research Center, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Cardiac and Cerebral Vascular Research Center, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Jia-Guo
authors.initials: JG
authors.lastname: Zhou
authors.affiliation: Cardiac and Cerebral Vascular Research Center, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. Electronic address: tangyb@mail.sysu.edu.cn.
authors.forename: Yong-Bo
authors.initials: YB
authors.lastname: Tang
authors.affiliation: Cardiac and Cerebral Vascular Research Center, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. Electronic address: guanyy@mail.sysu.edu.cn.
authors.forename: Yong-Yuan
authors.initials: YY
authors.lastname: Guan
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D004705:Endocytosis; D005487:Foam Cells / Q000166:cytology*; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D064368:Healthy Volunteers; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007769:Lactams / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism; D008264:Macrophages / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051116:Receptors, Scavenger / Q000378:metabolism*; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry; D053778:Thiazolidines / Q000737:chemistry
chemical_list: D018955:CD36 Antigens; D047908:Intracellular Signaling Peptides and Proteins; D007769:Lactams; D008055:Lipids; D008077:Lipoproteins, LDL; D051116:Receptors, Scavenger; C105159:SH3GL1 protein, human; D051117:Scavenger Receptors, Class A; D013449:Sulfonamides; D053778:Thiazolidines; C099252:oxidized low density lipoprotein; C578512:pitstop 2; C074292:ikarugamycin
keywords: ASK1; Endophilin-A2; Foam cell formation; Scavenger receptor