Endoplasmic reticulum stress and the development of endothelial dysfunction

Abstract

The vascular endothelium plays a critical role in cardiovascular homeostasis, and thus identifying the underlying causes of endothelial dysfunction has important clinical implications. In this regard, the endoplasmic reticulum (ER) has recently emerged as an important regulator of metabolic processes. Dysfunction within the ER, broadly termed ER stress, evokes the unfolded protein response (UPR), an adaptive pathway that aims to restore ER homeostasis. Although the UPR is the first line of defense against ER stress, chronic activation of the UPR leads to cell dysfunction and death and has recently been implicated in the pathogenesis of endothelial dysfunction. Numerous risk factors for endothelial dysfunction can induce ER stress, which may in turn disrupt endothelial function via direct effects on endothelium-derived vasoactive substances or by activating other pathogenic cellular networks such as inflammation and oxidative stress. This review summarizes the available data linking ER stress to endothelial dysfunction.

Oxidative burden in familial hypercholesterolemia

“…OS was suggested to drive this process through impairment of cellular organelle functions and structure (Table ). In particular, endoplasmic reticulum stress and mitochondrial destruction in vascular and immune cells contribute to atherosclerotic plaque progression by modulating cell apoptosis and lipid peroxidation (Battson, Lee, & Gentile, ; Yang et al, ). Hypercholesterolemia has also been shown to exert direct and indirect effects on myocardial function characterized by impaired cardiac performance and contractile dysfunction.…”

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

“…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. Under physiologic conditions, the ER's protein load and folding capacity are in balance; however, ER overload produces an accumulation of misfolded proteins in the ER, leading to the activation of the unfolded protein response (UPR), a process that is known as ER stress 12.…”

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“…5,6 Although the original activation of the UPR can protect the cell against these adverse situations, sustained or excessive UPR is harmful and contributes to cell apoptosis. 7 Accumulation of unfolded proteins within the ER lumen can simultaneously lead to the overexpression of glucose-regulated protein 78 (GRP78/BiP) and C/EBP homologous protein (CHOP), and activate the caspase-12, a crucial protein related to cell apoptosis induced by ER stress. 8 Recent studies have revealed that ER stressinduced apoptosis plays an important role in the pathogenesis and development of many diseases.…”