Dietary compound α-asarone alleviates ER stress-mediated apoptosis in 7β-hydroxycholesterol-challenged macrophages

• Published in: Molecular nutrition & food research 2016-05, Vol.60 (5), p.1033-1047
• Main Authors: Park, Sin-Hye, Kang, Min-Kyung, Choi, Yean-Jung, Kim, Yun-Ho, Antika, Lucia Dwi, Lim, Soon Sung, Kang, Young-Hee
• Format: Article
• Language: English
• Subjects: 7β-hydroxycholesterol; Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Animals; Anisoles - pharmacology; Apoptosis - drug effects; Apoptosomes - antagonists & inhibitors; Apoptosomes - metabolism; Caspase 12 - genetics; Caspase 12 - metabolism; Cell Line; DNA Fragmentation - drug effects; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; Endoplasmic Reticulum Stress - drug effects; Endoribonucleases - genetics; Endoribonucleases - metabolism; ER stress; Hydroxycholesterols - toxicity; Macrophage apoptosis; Macrophages - cytology; Macrophages - drug effects; Mice; Perilla; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Signal Transduction; Unfolded protein response; X-Box Binding Protein 1 - genetics; X-Box Binding Protein 1 - metabolism; α-Asarone
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.201500750

Scope 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. Methods and results 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. Conclusion 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. α‐Asarone present in purple perilla blocks 7β‐hydroxycholesterol‐induced macrophage apoptosis through allaying ER stress‐specific signaling involving caspase 12 activation and CHOP induction. α‐Asarone blunts IRE1α‐mediated activation of the TRAF2‐ASK1‐JNK1/2 complex and disturbs PERK‐mediated signaling of ATF4‐CHOP elicited by 7β‐hydroxycholesterol.