HDLs inhibit endoplasmic reticulum stress and autophagic response induced by oxidized LDLs

Muller, C.; Salvayre, Robert; Nègre‐Salvayre, Anne; Vindis, Cécile

doi:10.1038/cdd.2010.149

Cited by 89 publications

(89 citation statements)

References 40 publications

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“…HDL and its subfractions offer important cytoprotection for endothelial cells in response to different proapoptotic stimuli. Attenuation of endothelial cell apoptosis by HDL involves inhibition of death receptor, mitochondrial, and endoplasmic reticulum signaling pathways (93)(94)(95)(96). Tumor necrosis factor ␣-induced apoptosis via death-receptor signaling is blocked by HDL via inhibition of CPP32-like protease activity (97 ).…”

Section: Antiapoptotic Effectsmentioning

confidence: 99%

The Changing Face of HDL and the Best Way to Measure It

Karathanasis¹,

Freeman

Gordon

et al. 2017

Clinical Chemistry

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BACKGROUND: HDL cholesterol (HDL-C) is a commonly used lipid biomarker for assessing cardiovascular health. While a central focus has been placed on the role of HDL in the reverse cholesterol transport (RCT) process, our appreciation for the other cardioprotective properties of HDL continues to expand with further investigation into the structure and function of HDL and its specific subfractions. The development of novel assays is empowering the research community to assess different aspects of HDL function, which at some point may evolve into new diagnostic tests. CONTENT:This review discusses our current understanding of the formation and maturation of HDL particles via RCT, as well as the newly recognized roles of HDL outside RCT. The antioxidative, antiinflammatory, antiapoptotic, antithrombotic, antiinfective, and vasoprotective effects of HDL are all discussed, as are the related methodologies for assessing these different aspects of HDL function. We elaborate on the importance of protein and lipid composition of HDL in health and disease and highlight potential new diagnostic assays based on these parameters.

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Section: Antiapoptotic Effectsmentioning

confidence: 99%

The Changing Face of HDL and the Best Way to Measure It

Karathanasis¹,

Freeman

Gordon

et al. 2017

Clinical Chemistry

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“…These initial observations have been extended and lipophagy now appears to be important in maintaining lipid homeostasis in a diverse set of cell types from neurons to fibroblasts (Singh et al, 2009;Liu & Czaja, 2013;Settembre & Ballabio, 2014). Here, we demonstrate an important role for endothelial autophagy in maintaining vascular lipid homeostasis.It has been previously observed that when endothelial cells in culture are exposed to OxLDL they respond with an increase in autophagosomes (Nowicki et al, 2007;Zhang et al, 2010;Muller et al, 2011;Menghini et al, 2014). In general, autophagic flux can be assessed by simultaneously analyzing the levels of LC3-II, which labels autophagosome membranes, and measuring the levels of p62, a protein cleared via autophagic degradation.…”

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confidence: 99%

“…It has been previously observed that when endothelial cells in culture are exposed to OxLDL they respond with an increase in autophagosomes (Nowicki et al, 2007;Zhang et al, 2010;Muller et al, 2011;Menghini et al, 2014). In general, autophagic flux can be assessed by simultaneously analyzing the levels of LC3-II, which labels autophagosome membranes, and measuring the levels of p62, a protein cleared via autophagic degradation.…”

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confidence: 99%

Intact endothelial autophagy is required to maintain vascular lipid homeostasis

et al. 2015

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SummaryThe physiological role of autophagic flux within the vascular endothelial layer remains poorly understood. Here, we show that in primary endothelial cells, oxidized and native LDL stimulates autophagosome formation. Moreover, by both confocal and electron microscopy, excess native or modified LDL appears to be engulfed within autophagic structures. Transient knockdown of the essential autophagy gene ATG7 resulted in higher levels of intracellular 125 I-LDL and oxidized LDL (OxLDL) accumulation, suggesting that in endothelial cells, autophagy may represent an important mechanism to regulate excess, exogenous lipids. The physiological importance of these observations was assessed using mice containing a conditional deletion of ATG7 within the endothelium. Following acute intravenous infusion of fluorescently labeled OxLDL, mice lacking endothelial expression of ATG7 demonstrated prolonged retention of OxLDL within the retinal pigment epithelium (RPE) and choroidal endothelium of the eye. In a chronic model of lipid excess, we analyzed atherosclerotic burden in ApoE À/À mice with or without endothelial autophagic flux. The absence of endothelial autophagy markedly increased atherosclerotic burden. Thus, in both an acute and chronic in vivo model, endothelial autophagy appears critically important in limiting lipid accumulation within the vessel wall. As such, strategies that stimulate autophagy, or prevent the agedependent decline in autophagic flux, might be particularly beneficial in treating atherosclerotic vascular disease.Key words: autophagy; lipids; atherosclerosis; mouse.Cardiovascular disease, driven in part by the accumulation of modified lipids within the vessel wall, represents the leading cause of death in developed nations (Go et al., 2013). Considerable attention and study has been directed at the molecular consequences following the subendothelial deposition of lipids. These consequences include the recruitment of inflammatory cells and the subsequent engulfment of this deposited subendothelial lipid by resident macrophages (Chinetti-Gbaguidi et al., 2014;Randolph, 2014). In contrast, relatively little is known regarding the steps proximal to lipid deposition and what regulatory role, if any, the endothelium might play in this process. While evidence is limited for the case of the endothelium, in other cell types it appears that autophagy may play a critical role in maintaining overall lipid homeostasis. For instance, mice bearing ATG5-deficient macrophages appear to exhibit increased plaque formation when bred with pro-atherogenic mouse strains (Liao et al., 2012;Razani et al., 2012). While the basis for this increased plaque burden is undoubtedly complex, evidence suggests that macrophage-specific ATG5 deletion results in impaired lipophagy (Sergin & Razani, 2014). Lipophagy refers to the specific degradation of lipids by the autophagic machinery. This concept was perhaps first described in the liver where genetic disruption of macroautophagy led to the accumulation of lipid droplets (Singh...

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“…It is well-known that autophagy occurs in advanced atherosclerotic plaques (4)(5)(6), and that macrophage autophagy exerts a protective effect in advanced atherosclerosis (7). Previous studies have shown that ox-LDL may induce autophagy in endothelial cells, leading to the degradation of ox-LDL through autolysosomes (8,9). However, little is currently known about whether ox-LDL may induce autophagy in macrophages.…”

Section: Introductionmentioning

confidence: 98%

Simvastatin enhances oxidized-low density lipoprotein-induced macrophage autophagy and attenuates lipid aggregation

Huang

Jin

Yan

et al. 2014

Molecular Medicine Reports

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Abstract. Macrophage autophagy exerts a protective effect in advanced atherosclerosis. It has previously been reported that oxidized low-density lipoprotein (ox-LDL) induces autophagy in endothelial cells, and simvastatin enhances autophagy in coronary arterial myocytes. However, it is currently unknown whether ox-LDL induces autophagy in macrophages, or whether simvastatin affects macrophage autophagy in atherosclerosis. The present study demonstrated that ox-LDL induced lipid accumulation in the J774A.1 macrophage cell line, in a dose-dependent manner, as determined by oil red O staining. Ox-LDL also induced autophagy in the J774A.1 cells, by converting microtubule-associated protein 1 light chain 3 (LC3) I to LC3 II, which is a well-known autophagy marker. Notably, treatment of the cells with simvastatin elevated ox-LDL-induced macrophage autophagy, this was detected through the conversion of LC3 I to LC3 II and the increased expression of Beclin1, another autophagy marker. Furthermore, it was shown that stimulation with ox-LDL led to the redistribution of green fluorescent protein (GFP)-LC3 from diffusion distribution, to the formation of puncta in the J774A.1 cells. Simvastatin promoted the ox-LDL-induced formation of GFP-LC3 puncta, as detected by confocal laser scanning microscopy. Simvastatin was also shown to inhibit ox-LDL-induced cholesterol accumulation in the J774A.1 cells, as observed by oil red O staining and CHOD-PAP assay. These results suggest that simvastatin may enhance ox-LDL-induced macrophage autophagy and attenuate lipid aggregation. IntroductionActivation, dysfunction and structural alterations of the arterial endothelium results in the subendothelial retention of oxidized low-density lipoprotein (ox-LDL) from the plasma, thereby promoting the development and progression of atherosclerosis (1). Activated endothelial cells secrete chemokines, and subsequently express adhesion molecules, which may facilitate the recruitment of leukocytes, from the blood into the arterial wall (2). Of the leukocytes, monocytes are a critical cell type that contribute to the formation of atherosclerotic plaques. In the intima, migrated monocytes differentiate into macrophages, which engulf ox-LDL to form cholesterol-laden foam cells (3).Autophagy is a conserved catabolic process in which cytoplasmic material is delivered to the lysosomal machinery for degradation and recycling. It is well-known that autophagy occurs in advanced atherosclerotic plaques (4-6), and that macrophage autophagy exerts a protective effect in advanced atherosclerosis (7). Previous studies have shown that ox-LDL may induce autophagy in endothelial cells, leading to the degradation of ox-LDL through autolysosomes (8,9). However, little is currently known about whether ox-LDL may induce autophagy in macrophages.Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Statins impede cholesterol biosynthesis, therefore reducing blood cholesterol levels. As well as lowering lipid levels, statins have been demons...

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HDLs inhibit endoplasmic reticulum stress and autophagic response induced by oxidized LDLs

Cited by 89 publications

References 40 publications

The Changing Face of HDL and the Best Way to Measure It

The Changing Face of HDL and the Best Way to Measure It

Intact endothelial autophagy is required to maintain vascular lipid homeostasis

Simvastatin enhances oxidized-low density lipoprotein-induced macrophage autophagy and attenuates lipid aggregation

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