Abstract
The endoplasmic reticulum (ER) stress is an important event in the pathogenesis of different human disorders, including atherosclerosis. ER stress leads to disturbance of cellular homeostasis, apoptosis, and in the case of macrophages, to foam cell formation and pro-inflammatory cytokines production. In atherosclerosis, several cell types can be affected by ER stress, including endothelial cells, vascular smooth muscular cells, and macrophages. Modified low-density lipoproteins (LDL) and cytokines, in turn, can provoke ER stress through different processes. The signaling cascades involved in ER stress initiation are complex and linked to other cellular processes, such as lysosomal biogenesis and functioning, autophagy, mitochondrial homeostasis, and energy production. In this review, we discuss the underlying mechanisms of ER stress formation and the interplay of lipid accumulation and pro-inflammatory response. We will specifically focus on macrophages, which are the key players in maintaining chronic inflammatory milieu in atherosclerotic lesions, and also a major source of lipid-accumulating foam cells.
Highlights
Atherosclerosis is a chronic disease, which is associated with lipid accumulation and inflammation in large and medium-sized arteries [1]
Cause prolonged endoplasmic reticulum (ER)-stress, which induces the macrophage apoptosis via activation of CCAAT/enhancer-binding protein-homologous protein (CHOP) through inositol requiring protein 1α (IRE1α)/Jun amino-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK), IRE1α/X-box binding protein 1 (XBP1), activating transcription factor 6 (ATF6)/XBP1, and protein kinase RNA-like ER kinase (PERK)/eIF2α/activating transcription factor 4 (ATF4) pathways
Activation of ER stress by endogenous lipids in cells leads to increased expression of the markers unfolded protein response (UPR), Thioredoxin-interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3), and IL-1β, which indicates the development of pro-inflammatory response in macrophages via the ER/TXNIP/NLRP3 stress pathway [87]
Summary
Atherosclerosis is a chronic disease, which is associated with lipid accumulation and inflammation in large and medium-sized arteries [1]. Macrophages, as well as other cell types of the arterial wall, change their appearance upon lipid accumulation, becoming so-called foam cells These processes are currently well documented, the exact mechanisms that mediate foam cell formation and pro-inflammatory cytokines release, remain to be fully understood. We will focus on macrophages, since these cells play a key role in maintaining pro-inflammatory conditions in atherosclerotic lesions, and are the major source of foam cells that are responsible for lipid accumulation in the plaque. ER stress associated with unfolded protein response (UPR) may lead to the induction of inflammatory response, lipid accumulation, and/or apoptosis [9]. The activated PERK serine-threonine kinase launches the first UPR pathway by phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2α) that leads to the arrest of protein translation and induction of selective mRNAs translation, including activating transcription factor 4 (ATF4). NF-κB induces the expression of various pro-inflammatory cytokines, such as TNF-α and interleukin (IL)-6, leading to pro-inflammatory response [22]
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