Endothelin-1–Induced Endoplasmic Reticulum Stress in Disease

Abstract

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) represents a cellular stress induced by multiple stimuli and pathologic conditions. Recent evidence implicates endothelin-1 (ET-1) in the induction of placental ER stress in pregnancy disorders. ER stress has previously also been implicated in various other disease states, including neurodegenerative disorders, diabetes, and cardiovascular diseases, as has ET-1 in the pathophysiology of these conditions. However, to date, there has been no investigation of the link between ET-1 and the induction of ER stress in these disease states. Based on recent evidence and mechanistic insight into the role of ET-1 in the induction of placental ER stress, the following review attempts to outline the broader implications of ET-1-induced ER stress, as well as strategies for therapeutic intervention based around ET-1. Endoplasmic Reticulum StressThe endoplasmic reticulum (ER) is a multifunctional organelle involved in the synthesis, folding, and post-translational modification of membrane and secretory proteins. In addition, the ER also serves as a reservoir of calcium ions (Ca 21 ) (Zhang and Kaufman, 2008). In the ER lumen, Ca 21 is buffered by calcium-binding proteins. Many of these proteins also serve as molecular chaperones involved in the folding and quality control of ER proteins, and their functional activity alters with changes in Ca 21 concentration (Michalak et al., 1998). Growth factors, hormones, and stimuli that perturb cellular energy levels, nutrient availability, or redox status all affect ER calcium storage. Loss of ER Ca 21 homeostasis suppresses posttranslational modifications of proteins in the ER. As a result, misfolded proteins accumulate, provoking ER stress response pathways known collectively as the unfolded protein response (UPR) (Brostrom and Brostrom, 2003).The UPR is induced to restore ER homeostasis. It reduces the burden of new proteins entering the ER lumen through attenuation of translation, enhances the protein folding capacity by increasing ER chaperone proteins [glucose-regulated protein78 (GRP78) and GRP94] and folding enzymes, and promotes degradation of remaining unfolded or misfolded proteins through increased capacity of the cytosolic ubiquitin-proteasome system (Brostrom and Brostrom,

Endothelin-1 traps potently reduce pathologic markers back to basal levels in an in vitro model of diabetes

“…Both proteins were significantly increased in HRMECs after 48 h incubation with HG and 24 h incubation with ET-1 compared to HRMECs treated with normal glucose (5 mM, NG) and were prevented following incubation with ET-traps (monomer). * Statistically significant compared to NG, ** statistically significant compared to HG or ET-1, experiment performed in triplicate from three separate experiments, data expressed as mean ± SD, normalized to NG (5 mM glucose) [24][25][26], further studies could also investigate the efficacy of ET-traps in these areas.…”

AQP1 suppression by ATF4 triggers trabecular meshwork tissue remodelling in ET‐1‐induced POAG

“…ET‐1 has been reported to induce ER stress and plays a role in inflammatory diseases, pregnancy disorders, neurodegenerative diseases and POAG . Several transcription factors, such as ATF4, NFkB, eIF2a and XBP1s, are activated during ER stress .…”

Endothelin-1 Serum Concentration is Lower in Children and Adolescents with High Myopia, a Preliminary Study

“…As a result of axial eyeball growth in patients with high myopia, laminar blood flow as well as retinal vascular tone are disturbed. Consequently, it affects the vascular shear stress, which is necessary to form the active ET-1 peptide [7], responsible for vasoconstriction. At a later stage, ET-1 releases NO leading to permanent tonic vasodilation [29].…”

“…As a result of transcription, proendothelin-1 is formed. Subsequent stimulation by hypoxia or vascular wall shear stress with the participation of an endothelin-converting enzyme leads to the formation of an active peptide [7]. ET-1 exerts its effects by binding to the endothelin receptors A (ETA) and B (ETB), two cell surface proteins that belong to the G-protein-coupled receptors superfamily.…”