α-Asarone blocks 7β-hydroxycholesterol-exposed macrophage injury through blocking elF2α phosphorylation and prompting beclin-1-dependent autophagy.

α-Asarone blocks 7β-hydroxycholesterol-exposed macrophage injury through blocking elF2α phosphorylation and prompting beclin-1-dependent autophagy.

Oncotarget. 2017 Jan 09;:

Authors: Park SH, Kang MK, Choi YJ, Kim YH, Antika LD, Kim DY, Lee EJ, Lim SS, Kang YH

Abstract
Macrophage apoptosis is salient in advanced atherosclerotic lesions and is induced by several stimuli including endoplasmic reticulum (ER) stress. This study examined that α-asarone present in purple perilla abrogated macrophage injury caused by oxysterols via ER stress- and autophagy-mediated mechanisms. Nontoxic α-asarone at 1-20 μM attenuated 7β-hydroxycholesterol-induced activation of eukaryotic initiation factor 2α in macrophages leading to C/EBP homologous protein (CHOP) expression and apoptosis due to sustained ER stress. The α-asarone treatment increased the formation of autophagolysosomes localizing in perinuclear regions of 7β-hydroxycholesterol-exposed macrophages. Consistently, this compound promoted the induction of the key autophagic proteins of beclin-1, vacuolar protein sorting 34 and p150 responsible for vesicle nucleation, and prompted the conversion of microtubule-associated protein 1A/1B-light chain 3 and the induction of p62, neighbor of BRCA1 and autophagy-related (Atg) 12-Atg5-Atg16L conjugate involved in phagophore expansion and autophagosome formation. Additionally, α-asarone increased ER phosphorylation of bcl-2 facilitating beclin-1 entry to autophagic process. Furthermore, the deletion of Atg5 or beclin-1 gene enhanced apoptotic CHOP induction. Collectively, α-asarone-stimulated autophagy may be potential multi-targeted therapeutic avenues in treating ER stress-associated macrophage apoptosis.

PMID: 28088783 [PubMed - as supplied by publisher]

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