Premium
Nucleotide‐binding oligomerization domain protein 2 deficiency enhances CHOP expression and plaque necrosis in advanced atherosclerotic lesions
Author(s) -
Kwon MinYoung,
Hwang Narae,
Back Sung Hoon,
Lee SeonJin,
Perrella Mark A.,
Chung Su Wol
Publication year - 2020
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.15294
Subject(s) - unfolded protein response , nod2 , chop , atf6 , endoplasmic reticulum , activating transcription factor , microbiology and biotechnology , transcription factor , vascular smooth muscle , cancer research , biology , transactivation , chemistry , endocrinology , immunology , genetics , immune system , smooth muscle , gene , innate immune system
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.