Self-eating in the plaque: what macrophage autophagy reveals about atherosclerosis

Sergin, Ismail; Razani, Babak

doi:10.1016/j.tem.2014.03.010

Cited by 99 publications

(99 citation statements)

References 100 publications

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“…Previous studies have also suggested that the atherosclerotic plaque is enriched for autophagosomes (Martinet & De Meyer, 2009). In addition, recent mouse genetic studies have implicated the role of autophagy in macrophage foam cell formation (Muller et al, 2011;Ouimet et al, 2011;Le Guezennec et al, 2012;Razani et al, 2012;Sergin & Razani, 2014). Our results complement these observations and suggest that similar to what was observed in macrophages, endothelial autophagy is important in limiting atherosclerotic progression.…”

supporting

confidence: 89%

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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confidence: 89%

Intact endothelial autophagy is required to maintain vascular lipid homeostasis

et al. 2015

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“…The mTOR signaling pathway provides a direct metabolic link between immune cells and microenvironment, but the immunologic regulation due to mTOR inhibition is complex and cell type dependent (24,25). In monocytes and macrophages, mTORC1 inhibitors such as rapamycin and everolimus appear to evoke pro-and antiinflammatory cytokine production (25,41), macrophage polarization (42) and autophage (43). Targeting mTOR signaling pathway via FRs may be a useful approach to curtail autoimmune and other diseases caused or worsened by activated macrophages.…”

Section: Discussionmentioning

confidence: 99%

Antiinflammatory Activity of a Novel Folic Acid Targeted Conjugate of the mTOR Inhibitor Everolimus

Parker

Kleindl

et al. 2015

Mol Med

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“…Studying rapalog-treated atherosclerotic mice with a deficiency in macrophage autophagy (eg, ATG5 deficient), mTORC1 (eg, Raptor deficient), or mTORC2 (eg, Rictor deficient) will provide further insights in the specificity and the regulation of macrophage autophagy in atherosclerotic plaques. 93 Everolimus eluting fully biodegradable vascular scaffolds are now being used in clinical trials with extraordinary results.…”

Section: Stent-based Delivery Of Rapamycin and Rapalogsmentioning

confidence: 99%

Autophagy in Vascular Disease

Meyer

Grootaert

Michiels

et al. 2015

Circulation Research

254

179

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A utophagy is a complex intracellular process that delivers cytoplasmic constituents for degradation into lysosomes.1,2 Three main types of autophagy have been described: (1) microautophagy, comprising direct engulfment of cytoplasmic material by lysosomes via inward invaginations of the lysosomal membrane, (2) macroautophagy, characterized by formation of double-membrane sequestering compartments termed autophagosomes that fuse with lysosomes for delivery of cytoplasmic cargo, and (3) chaperone-mediated autophagy, mediated by a chaperone complex and lysosomal-associated membrane protein type 2A to degrade cytosolic proteins with a specific targeting motif. The term autophagy usually refers to macroautophagy, which is the most prevalent and beststudied form of autophagy. Also in this review, we will focus exclusively on macroautophagy, further cited as autophagy.Autophagy occurs at basal levels in most tissues to allow constitutive turnover of cytosolic components but is stimulated by environmental stress-related signals (eg, nutrient deprivation and oxidative injury) to recycle nutrients and to generate energy for maintenance of cell viability in unfavorable conditions.1 In addition to cellular stress, basal autophagy can be intensified by specific drugs, 3 indicating that the autophagic machinery is a potential therapeutic target for diverse diseases. Indeed, given that autophagy is involved in the prevention

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Self-eating in the plaque: what macrophage autophagy reveals about atherosclerosis

Cited by 99 publications

References 100 publications

Intact endothelial autophagy is required to maintain vascular lipid homeostasis

Intact endothelial autophagy is required to maintain vascular lipid homeostasis

Antiinflammatory Activity of a Novel Folic Acid Targeted Conjugate of the mTOR Inhibitor Everolimus

Autophagy in Vascular Disease

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