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

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 À/À ApoE À/À mice. Our findings indicate an unsuspected critical role for NOD2 in ER stress-induced cell death.Abbreviations ATF6, activating transcription factor 6; CHOP, transcription factor C/EBP homologous protein; ER stress, endoplasmic reticulum stress; ERSE, cis-acting ER stress response element; IREl, inositol requiring protein 1; LRRs, leucine-rich repeats; MDP, muramyl dipeptide; NOD2, nucleotide-binding oligomerization domain protein 2; PERK, protein kinase RNA-like endoplasmic reticulum kinase; PRRs, pattern recognition receptors; TLRs, toll-like receptors; VSMCs, vascular smooth muscle cells; XBP1, X-box binding protein 1.NOD2 regulates ER stress-induced cell death M-Y. Kwon et al.

RNA-seq analysis of extracellular vesicles from hyperphosphatemia-stimulated endothelial cells provides insight into the mechanism underlying vascular calcification

“…Our analysis demonstrated that those target mRNAs for hsa-miR-3182 included NOD2, ZCCHC14, DMTF1, STAM2, SLC22A25, AOAH, KIAA1109, HECTD4, SOGA3, RBM47, ADGRL3, PTPRT, KIAA0408, SLC16A7, PSTPIP1. In consistent with our results, several lines of evidence demonstrated that NOD2 deficiency enhanced pulmonary VSMC proliferation, and exacerbated plaque necrosis in advanced atherosclerotic lesions [ 28 , 29 ]. Furthermore, Sanneke et al observed that SLC22A25 gene had strong signals associated with plaque morphology [ 30 ].…”

NOD1 and NOD2 in inflammatory and infectious diseases

“…NOD2‐deficient VSMCs also enhance ER stress‐induced cell death 218 . Finally, NOD2 ablation promoted disruption of atherosclerotic lesions in ApoE ‐/‐ mice under an atherogenic diet 218 . These data demonstrated a possible protective role of NOD2 during ER stress‐induced VSMC death in processes related to plaque necrosis and progression of atherosclerotic lesions.…”

“…NOD2 is expressed in VSMCs 216 and plays protective effects in a vascular injury model of neointima hyperplasia by promoting VSMC proliferation, migration, and neointimal formation after vascular injury 217 . NOD2‐deficient VSMCs also enhance ER stress‐induced cell death 218 . Finally, NOD2 ablation promoted disruption of atherosclerotic lesions in ApoE ‐/‐ mice under an atherogenic diet 218 .…”

Endoplasmic reticulum stress-mediated cell death in cardiovascular disease

“… 66 Nucleotide-binding oligomerization domain protein 2 interacts with the ERS sensor molecule ATF6 and acts as a negative regulator of ATF6 activation and its downstream target molecule CHOP, thereby regulating ERS-induced apoptosis. 67 Furthermore, ATF6 induces the transcription factor XBP1. 68 Transcription factor XBP1 directly activates the transcription of UPR target genes, such as CHOP, GRP78, and XBP1, exerting a prosurvival effect.…”