title: Dietary compound α-asarone alleviates ER stress-mediated apoptosis in 7β-hydroxycholesterol-challenged macrophages.
abstract: Prolonged endoplasmic reticulum (ER) stress has lost the function of protein folding capacity and the ER accumulation of unfolded proteins that eventually triggers apoptosis. Oxysterols are emerging as contributing factors in atherogenesis known to involve macrophage apoptosis. This study determined the inhibitory effect of α-asarone present in purple perilla, on 7β-hydroxycholesterol-induced macrophage apoptosis, targeting against ER stress signaling pathway.
  
  
  
  J774A1 murine macrophages were exposed to 28 μM 7β-hydroxycholesterol and treated with 1-10 μM α-asarone. Macrophage apoptosis and ER stress were examined by and α-Asarone blocked 7β-hydroxycholesterol-induced DNA fragmentation and apoptosome formation. Immunoblotting showed that the oxysterol activated the ER transmembrane resident kinases of IRE1α, PERK and ATF4 and triggered caspase-12 signaling cascades, which was reversed by α-asarone. Additionally, 7β-hydroxycholesterol activated TRAF2-ASK1-JNK1/2 complex following the IRE1α activation, and α-asarone blunted such IRE1α-mediated pathway. Real-time PCR and dual-luciferase reporter analyses revealed that α-asarone reduced transcriptional activation of ER stress-responsive genes including XBP1 and CHOP by 7β-hydroxycholesterol. Finally, α-asarone disturbed oxysterol-elicited signaling of PERK and ATF4 responsible for CHOP induction.
  
  
  
  α-Asarone blocked 7β-hydroxycholesterol-induced macrophage apoptosis through allaying ER stress-specific signaling involving caspase activation and CHOP induction. α-Asarone was an anti-atherosclerotic agent antagonizing ER stress-mediated macrophage apoptosis by 7β-hydroxycholesterol.
authors.affiliation: Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Sin-Hye
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Min-Kyung
authors.initials: MK
authors.lastname: Kang
authors.affiliation: Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Yean-Jung
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Yun-Ho
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Lucia Dwi
authors.initials: LD
authors.lastname: Antika
authors.affiliation: Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Soon Sung
authors.initials: SS
authors.lastname: Lim
authors.affiliation: Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea.
authors.forename: Young-Hee
authors.initials: YH
authors.lastname: Kang
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000081248:Allylbenzene Derivatives; D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053478:Apoptosomes / Q000037:antagonists & inhibitors / Q000378:metabolism; D053454:Caspase 12 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D053938:DNA Fragmentation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D006888:Hydroxycholesterols / Q000633:toxicity*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D051701:Activating Transcription Factor 4; D000081248:Allylbenzene Derivatives; D000840:Anisoles; D053478:Apoptosomes; D053454:Caspase 12; D004722:Endoribonucleases; D006888:Hydroxycholesterols; D017346:Protein Serine-Threonine Kinases; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C081452:Atf4 protein, mouse; C000605544:Xbp1 protein, mouse; C012195:asarone; C011724:cholest-5-en-3 beta,7 alpha-diol; C510185:Ern1 protein, mouse; C506440:Casp12 protein, mouse
keywords: 7β-hydroxycholesterol; ER stress; Macrophage apoptosis; Unfolded protein response; α-Asarone