Activated IRE1recruits TRAF2, which interacts with JNK and IKK, and subsequently phosphorylates and activates downstream inflammatory pathways [85]. pathogenesis of atherosclerosis is a complex process involving a variety of metabolic and signaling pathways. Several known risk factors include metabolic disorders, dyslipidemia, hyperglycemia, hypertension, and elevated homocysteine (Hcy) levels [3C5]. The formation and development of atherosclerotic lesions involve the pathological processes of lipid accumulation in the arterial wall, local inflammatory processes, and endothelial dysfunction [6, 7]. Increasing evidence indicates that endoplasmic reticulum (ER) stress signaling pathways play important roles in atherosclerosis and its MPO-IN-28 related CVDs. The ER is an organelle in eukaryotic cells that is important for protein synthesis, folding, and transport; lipid synthesis; and calcium homoeostasis Rabbit polyclonal to Amyloid beta A4.APP a cell surface receptor that influences neurite growth, neuronal adhesion and axonogenesis.Cleaved by secretases to form a number of peptides, some of which bind to the acetyltransferase complex Fe65/TIP60 to promote transcriptional activation.The A [8]. Various pathological factors, such as hyperlipidemia, oxidative stress, and calcium imbalance, may lead to perturbations in ER homeostasis, which are manifested as the accumulation of unfolded or misfolded proteins in the ER lumen, causing ER stress [9, 10]. Chronic ER stress is associated with the development of atherosclerosis through a variety of mechanisms. This pathological process may involve ER stress mediating the activation of inflammatory response mechanisms and apoptotic signaling pathways. This affects lipid metabolism, leading to cell dysfunction and affecting the formation and stability of atherosclerotic plaques, all of which are important conditions for atherosclerosis development [11C14]. At the same time, considering the important roles of ER stress signaling pathways and their mediation of multiple pathologic pathways, targeting ER stress pathways may be a promising therapeutic strategy for atherosclerosis and CVDs. In this review, we discuss the role of ER stress in atherosclerosis and its potential as a therapeutic target. 2. ER Stress and Unfolded Protein Response (UPR) In order to protect ER functional integrity and cell homeostasis, UPR, an evolutionarily conserved signaling cascade, is activated upon ER stress [15, 16]. The main mechanism is known to involve activation of three stress sensors located on the ER membrane: protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 MPO-IN-28 (IRE1), and activating transcription factor 6 (ATF6) [17]. In the unstressed state, the UPR remains inactive through the binding of the 78?kDa glucose-regulated protein (BiP/GRP78) to the lumen domains of the MPO-IN-28 three pivotal ER transmembrane proteins mentioned above [18]. When unfolded or misfolded proteins accumulate in the ER lumen, BiP/GRP78 dissociates to assist in the folding process, thus initiating the UPR signaling cascade. GRP78 dissociation is the current mainstream view of UPR activation, but other unknown mechanisms may also be involved [19]. As an initial response to ER stress, the UPR regulates and restores ER function mainly by blocking protein translation, upregulating ER chaperone proteins, facilitating protein folding, and guiding misfolded proteins into the correct degradation pathway [8]. PERK is activated by autophosphorylation after dissociation from BiP/GRP78. At the early stage of the ER stress response, the UPR first reduces protein overload through activated PERK (phospho-PERK)-mediated eukaryotic initiation factor 2(eIF2regulates the translation of certain mRNAs including activating transcription factor 4 (ATF4). ATF4, ATF6, and XBP1 are associated with the expression of C/EBP-homologous protein (CHOP), a widely studied biomarker involved in the ER stress-associated apoptosis signaling pathway [24, 25]. When the UPR fails to normalize ER function, long-term ER stress causes activation of apoptosis and inflammatory response pathways. 3. Proatherogenic Effects of ER Stress in Different Cell Types 3.1. ER Stress in Endothelial Cells (ECs) The theory of the injury response of vascular endothelial cells (VECs) is one of the most recognized pathogenesis models of atherosclerosis. Endothelial dysfunction plays a role as an initiating factor in atherosclerosis. Atherosclerosis occurs most often in areas of turbulent blood flow, such as vessel bending or branching [26]. ECs experience a constant strain of blood flow and are particularly susceptible in these areas. Evidence from nonatherosclerotic swine suggested that the ER stress markers IRE1, XBP1, and ATF6 are activated in ECs in atherosclerotic-susceptible areas of the aorta [27]. Recently, studies have found that disturbed blood flow with.