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Review
. 2019 Apr 3;20(7):1658.
doi: 10.3390/ijms20071658.

Endoplasmic Reticulum Stress: A Critical Molecular Driver of Endothelial Dysfunction and Cardiovascular Disturbances Associated with Diabetes

Hatem Maamoun  1 , Shahenda S Abdelsalam  2 , Asad Zeidan  3 , Hesham M Korashy  4 , Abdelali Agouni  5
Affiliations
Review

Endoplasmic Reticulum Stress: A Critical Molecular Driver of Endothelial Dysfunction and Cardiovascular Disturbances Associated with Diabetes

Hatem Maamoun et al. Int J Mol Sci. .

Abstract

Physical inactivity and sedentary lifestyle contribute to the widespread epidemic of obesity among both adults and children leading to rising cases of diabetes. Cardiovascular disease complications associated with obesity and diabetes are closely linked to insulin resistance and its complex implications on vascular cells particularly endothelial cells. Endoplasmic reticulum (ER) stress is activated following disruption in post-translational protein folding and maturation within the ER in metabolic conditions characterized by heavy demand on protein synthesis, such as obesity and diabetes. ER stress has gained much interest as a key bridging and converging molecular link between insulin resistance, oxidative stress, and endothelial cell dysfunction and, hence, represents an interesting drug target for diabetes and its cardiovascular complications. We reviewed here the role of ER stress in endothelial cell dysfunction, the primary step in the onset of atherosclerosis and cardiovascular disease. We specifically focused on the contribution of oxidative stress, insulin resistance, endothelial cell death, and cellular inflammation caused by ER stress in endothelial cell dysfunction and the process of atherogenesis.

Keywords: atherosclerosis; diabetes; endoplasmic reticulum stress; endothelial dysfunction; unfolded protein response.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Unfolded protein response (UPR). Upon the buildup of misfolded and/or unfolded proteins inside the endoplasmic reticulum (ER), the chaperone, binding immunoglobulin protein (BiP), dissociates from and, thus, activating the three ER transmembrane proteins, protein kinase-like endoplasmic reticulum kinase (PERK), activating transcription factor (ATF)-6, and inositol requiring enzyme (IRE)-1α. Activated PERK phosphorylates eukaryotic initiation factor (eIF)-2α blunting, thus, general translation of proteins with the selective synthesis of transcription factor, ATF-4, being allowed. Free ATF-6 transfers to the Golgi apparatus where it gets cleaved and, hence, activated. Activated cleaved ATF-6 relocates to the nucleus and boosts the transcription of molecular chaperones that can help in improving ER protein folding functions. Activated IRE-1α causes the mRNA splicing of X-box binding protein (XBP)-1 and generates an active splice variant (sXBP-1) which stimulates the transcription of genes controlling the expression of several molecular chaperones, foldases, and proteins the ER-associated degradation (ERAD) machinery aiming at restoring ER homeostasis. Prolonged activation of UPR leads to ER stress with activation of inflammatory signaling pathways, including c-Jun N-terminal Kinase (JNK) and nuclear factor (NF)-κB, which may activate pro-inflammatory and apoptotic signals, such as CCAAT/enhancer-binding protein homologous protein (CHOP).
Figure 2
Figure 2
ER stress-induced apoptotic signaling pathways. Tumor necrosis factor-α receptor associated factor (TRAF-2) and apoptosis signal-regulating kinase (ASK)-1 are recruited by IRE-1α triggering the activation of JNK and p38 mitogen-activated protein kinase (MAPK). Activated JNK transfers to the mitochondrial membrane where it concomitantly activates Bim and inhibits Bcl-2. Active p38 MAPK will phosphorylate and, hence, activate CHOP, which in turn, stimulates the transcription of genes involved in apoptosis, such as ER oxidoreductase (ERO)-1α. Bax and Bak also interact and, hence, activate IRE-1α leading to depletion of Ca2+ ER stores. Via its kinase activity, PERK phosphorylates the elongation factor, elF-2α, and, hence, reduces general protein translation while allowing selective translation of specific genes ding JNK and NF-κB, which may activate pro-inflammatory and apoptotic signals, such as CHOP.
Figure 3
Figure 3
Activation of NF-κB by PERK and ATF-6. The activation of the PERK/eIF-2α axis leads to a severe reduction in protein translation, which decreases the expression levels of IκB protein. Subsequently, the ratio of NF-κB to IκB increases resulting in NF-κB activation. This is associated with a preferential increase in ATF-4 translation and synthesis. ATF-4 induces CHOP, which in turn, causes the induction of the pro-inflammatory cytokine interleukin (IL)-23. The activation of CHOP can also negatively regulate the activity of NF-κB and JNK, thus, affecting the activity of AP-1 downstream. The ER stress effector IRE-1α, activates TRAF-2. This activation complex can then activate IκB kinase (IKK), which in turn, causes IκB degradation and allows free NF-κB to stimulate mRNA expression of inflammatory genes. IRE-1α/TRAF-2 activates JNK, which consequently phosphorylates and, hence, activates the transcription factor AP-1. ATF-6 can induce ER stress-mediated inflammation by leaving the ER and translocating to the Golgi complex to undergo proteolytic cleavage and activation. Active ATF-6 fragments are able to transcribe APR-associated genes, such as those encoding the acute-phase proteins (APPs).
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