Nucleotide-binding oligomerization domain protein 2 deficiency enhances CHOP expression and plaque necrosis in advanced atherosclerotic lesions

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Title
Nucleotide-binding oligomerization domain protein 2 deficiency enhances CHOP expression and plaque necrosis in advanced atherosclerotic lesions
Author(s)
M Y Kwon; N Hwang; S H Back; Seon-Jin Lee; M A Perrella; S W Chung
Bibliographic Citation
FEBS Journal, vol. 287, no. 10, pp. 2055-2069
Publication Year
2020
Abstract
Endoplasmic reticulum (ER) stress-induced cell death of vascular smooth muscle cells (VSMCs) is extensively involved in atherosclerotic plaque stabilization. We previously reported that nucleotide-binding oligomerization domain protein 2 (NOD2) participated in vascular homeostasis and tissue injury. However, the role and underlying mechanisms of NOD2 remain unknown in ER stress-induced cell death of VSMC during vascular diseases, including advanced atherosclerosis. Here, we report that NOD2 specifically interacted with ER stress sensor activating transcription factor 6 (ATF6) and suppressed the expression of proapoptotic transcription factor CHOP (C/EBP homologous protein) during ER stress. CHOP-positive cells were increased in neointimal lesions after femoral artery injury in NOD2-deficient mice. In particular, a NOD2 ligand, MDP, and overexpression of NOD2 decreased CHOP expression in wild-type VSMCs. NOD2 interacted with an ER stress sensor molecule, ATF6, and acted as a negative regulator for ATF6 activation and its downstream target molecule, CHOP, that regulates ER stress-induced apoptosis. Moreover, NOD2 deficiency promoted disruption of advanced atherosclerotic lesions and CHOP expression in NOD2-/- ApoE-/- mice. Our findings indicate an unsuspected critical role for NOD2 in ER stress-induced cell death.
Keyword
ATF6cell deathCHOPER stressNOD2
ISSN
1742-464X
Publisher
Wiley
DOI
http://dx.doi.org/10.1111/febs.15294
Type
Article
Appears in Collections:
Division of Research on National Challenges > Environmental diseases research center > 1. Journal Articles
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