The role of endoplasmic reticulum stress in the progression of atherosclerosis

Abstract

Prolonged activation of the endoplasmic reticulum (ER) stress pathway known as the unfolded protein response (UPR) can lead to cell pathology and subsequent tissue dysfunction. There is now ample evidence that the UPR is chronically activated in atherosclerotic lesional cells, particularly advanced lesional macrophages and endothelial cells. The stressors in advanced lesions that can lead to prolonged activation of the UPR include oxidative stress, oxysterols, and high levels of intracellular cholesterol and saturated fatty acids. Importantly, these arterial wall stressors may be especially prominent in the settings of obesity, insulin resistance, and diabetes, all of which promote the clinical progression of atherosclerosis. In the case of macrophages, prolonged ER stress triggers apoptosis, which in turn leads to plaque necrosis if the apoptotic cells are not rapidly cleared. ER stress-induced endothelial cell apoptosis may also contribute to plaque progression. Another potentially important proatherogenic effect of prolonged ER stress is activation of inflammatory pathways in macrophages and, perhaps in response to atheroprone shear stress, endothelial cells. Although exciting work over the last decade has begun to shed light on the mechanisms and in vivo relevance of ER stress-driven atherosclerosis, much more work is needed to fully understand this area and to enable an informed approach to therapeutic translation.

Figure 1. Model of ER stress-induced apoptosis in advanced lesional macrophages

Advanced lesions contain a number of molecules and processes that are known ER stressors. Activation of the UPR in macrophages leads to elevated levels of CHOP, which through a pathway involving the CHOP target ERO1 and IP3R-mediated calcium release, leads to elevation in cytosolic calcium (Ca²⁺_i) and activation of CaMKII. CaMKII triggers apoptosis execution pathways through a number of mechanisms, including NADPH oxidase activation and subsequent ROS generation. In vivo evidence suggests that this scenario is necessary but not sufficient by itself for apoptosis. Rather, apoptosis in ER-stressed macrophages may require a “second hit” consisting of combinatorial pattern recognition receptor (PRR) activation, and there are many factors in advanced lesions that can activate PRRs. The mechanism by which PRR activation tips the balance toward apoptosis in ER-stressed macrophages involves amplification of apoptosis pathways, such as NADPH oxidase-mediated ROS generation, and suppression of ER stress-induced compensatory cell survival pathways. See text for details. (Illustration Credit: Cosmocyte/Cameron Slayden)

Figure 2. Possible roles of prolonged ER stress in early atherogenesis and advanced plaque progression

A, In early atherogenesis, extracellular matrix-retained and modified apoB-containing lipoproteins (LPs) trigger the expression of adhesion molecules and chemokines in endothelial cells (“EC activation”), leading to attraction of monocytes and other inflammatory cells to the nascent lesion. Early lesional endothelial cells, perhaps in response to disturbances in laminar blood flow at athero-susceptible sites, show evidence of ER stress, which may further promote EC activation. B, In advanced lesions, ER stress is prominent in macrophages (Mϕs) and can lead to inflammation and apoptosis in these cells. When apoptotic macrophages are not rapidly cleared by neighboring phagocytes, they become secondarily necrotic and lead to the generation of the necrotic core, a key feature of clinically dangerous plaques. ER stress in advanced lesions may also cause the death of endothelial cells, which may further amplify plaque progression and disruption, and of smooth muscle cells, which may contribute to the thinning of the protective fibrous cap. See text for details.