Prevention of atherosclerosis by the mTOR inhibitor everolimus in LDLR−/− mice despite severe hypercholesterolemia

Mueller, Marc; Beutner, Frank; Teupser, Daniel; Ceglarek, Uta; Thiery, Joachim

doi:10.1016/j.atherosclerosis.2007.09.019

Cited by 143 publications

(115 citation statements)

References 39 publications

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“…It is tempting to speculate that enhancing autophagy may therefore be a beneficial strategy to reduce the rate of age-dependent cardiovascular disease. Such speculation is supported by previous observations including that inhibition of mTOR (a kinase known to function as a negative regulator of autophagy) with pharmacological agents such as rapamaycin appears to inhibit atherosclerosis in a number of different animal models (Castro et al, 2004;Pakala et al, 2005;Mueller et al, 2008). Similarly, strategies such as calorie restriction, that are known to elevate autophagic flux, appear to reduce cardiovascular disease in both mice and humans (Guo et al, 2002;Fontana et al, 2004).…”

supporting

confidence: 53%

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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supporting

confidence: 53%

Intact endothelial autophagy is required to maintain vascular lipid homeostasis

et al. 2015

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“…In three separate studies involving apoE knockout mice or LDLR knockout mice, rapamycin reduces arteriosclerotic lesions despite the severe hypercholesterolemia in these mice, even when fed a high-fat diet. [29][30][31] Because the cardiovascular disease component of HGPS leads to devastating heart attacks or strokes, it will be of interest to examine if rapamycin confers any benefit on the cardiovascular aspects of HGPS by promoting clearance of progerin in cardiovascular tissues. The G608G mouse model of HGPS has a cardiovascular phenotype that shows improvement with FTI treatment.…”

Section: Rapamycin Promotes Clearance Of Progerinmentioning

confidence: 99%

Rapamycin activates autophagy in Hutchinson-Gilford progeria syndrome

Graziotto¹,

Cao²,

Collins³

et al. 2012

Autophagy

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“…mTOR inhibi tors prevent atherosclerosis in apo E-or LDLR -/--deficient mice despite hypercholesterolemia. [105][106][107] In humans, oral rapamycin prevents atherosclerotic re-stenosis.…”

mentioning

confidence: 99%

Rapamycin-induced glucose intolerance: Hunger or starvation diabetes

Blagosklonny

2011

Cell Cycle

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Prevention of atherosclerosis by the mTOR inhibitor everolimus in LDLR−/− mice despite severe hypercholesterolemia

Cited by 143 publications

References 39 publications

Intact endothelial autophagy is required to maintain vascular lipid homeostasis

Intact endothelial autophagy is required to maintain vascular lipid homeostasis

Rapamycin activates autophagy in Hutchinson-Gilford progeria syndrome

Rapamycin-induced glucose intolerance: Hunger or starvation diabetes

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