Endoplasmic reticulum stress and endothelial dysfunction

Abstract

Prolonged perturbation of the endoplasmic reticulum (ER) leads to ER stress and unfolded protein response (UPR) and contributes to the pathogenesis of various chronic disorders. This review focuses on the role of ER stress and UPR in endothelial cells and the relevance of these processes to vascular diseases. Chronic activation of ER stress and UPR pathways in endothelial cells leads to increased oxidative stress and inflammation, and often results in cell death. Because endothelial cells play a pivotal role in maintaining vascular homeostasis, various pathological conditions interfering with this homeostasis including homocysteinemia, hyperlipidimia, high glucose, insulin resistance, disturbed blood flow, and oxidative stress can lead to endothelial dysfunction in part through the activation of ER stress. We discuss recently discovered aspects of the role of ER stress/UPR in those pathological conditions. We also summarize recent findings implicating ER stress and UPR in systemic hypertension, as well as pulmonary arterial hypertension (PAH). Finally, this review will highlight a novel role of UPR mediators in the process of angiogenesis.

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

“…A number of experimental studies in cultured endothelial cells and in animal models suggest a role for ER stress in endothelial dysfunction 7. We were interested in whether acute stimulation of ER stress would produce similar effects in a healthy endothelium as the phenotype observed in the endothelium of patients with DM.…”

“…Over the past decade, the endoplasmic reticulum (ER) has emerged as an important regulator of metabolic processes and recently has been implicated in the pathogenesis of endothelial dysfunction 6, 7, 8. The ER is a large, membrane‐enclosed cellular compartment, critical to the physiologic regulation of many cellular processes, including protein folding, lipid biosynthesis and redox homeostasis 9, 10, 11.…”

In Vitro Study Examining the Activity of Vildagliptin and Sitagliptin against Hyperglycemia-Induced Effects in Human Umbilical Vein Endothelial Cells

“…Indeed, a recent in vivo study showed that the administration of the antioxidant vitamin C was able to improve both GLP-1 action and hyperglycemia control [5]. On the other hand, in endothelial cells, GLP-1 may counteract the high glucose-induced endoplasmic reticulum (ER) stress [7], which has been implicated in type 2 diabetes (T2D) and endothelial dysfunction [8,9]. Under ER stress, the unfolded protein response (UPR) is activated in order to restore normal ER homeostasis [8].…”

“…On the other hand, in endothelial cells, GLP-1 may counteract the high glucose-induced endoplasmic reticulum (ER) stress [7], which has been implicated in type 2 diabetes (T2D) and endothelial dysfunction [8,9]. Under ER stress, the unfolded protein response (UPR) is activated in order to restore normal ER homeostasis [8]. UPR acts by promoting the inhibition of protein synthesis, the degradation of misfolded proteins and the production of molecular chaperones involved in protein folding [8].…”

“…Under ER stress, the unfolded protein response (UPR) is activated in order to restore normal ER homeostasis [8]. UPR acts by promoting the inhibition of protein synthesis, the degradation of misfolded proteins and the production of molecular chaperones involved in protein folding [8]. A key player of UPR is immunoglobulin protein (BIP), a chaperone that usually maintains in the inactive form the three transmembrane sensors of ER stress: protein kinase RNA-like ER kinase (PERK), inositol requiring enzyme 1α (IRE-1 α) and activating transcription factor-6.…”