An activator of mTOR inhibits oxLDL-induced autophagy and apoptosis in vascular endothelial cells and restricts atherosclerosis in apolipoprotein E-/- mice

Peng, Nan; Meng, Na; Wang, ShengQing; Zhao, Fei; Zhao, Jingjing; Su, Le; Zhang, Shangli; Zhang, Yun; Zhao, Bao‐Xiang; Jiang, Miao

doi:10.1038/srep05519

Cited by 144 publications

(123 citation statements)

References 40 publications

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“…mTOR is a critical regulator of many fundamental features responding to upstream cellular signals and participating in the control of gene expression and cell behavior (33). Pharmacological intervention of mTORC1 with rapamycin has shown clear evidence of the value of mTOR inhibition in preventing the development of atherosclerosis and restenosis (34,35). Although mTORC1 has been linked to endothelial function and dysfunction, its downstream targets functioning in vascular dysregulation have not been examined in detail.…”

Section: Discussionmentioning

confidence: 99%

VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia

Zhu

Liu

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Vascular endothelial cells (ECs) at arterial branches and curvatures experience disturbed blood flow and induce a quiescent-to-activated phenotypic transition of the adjacent smooth muscle cells (SMCs) and a subsequent smooth muscle hyperplasia. However, the mechanism underlying the flow pattern-specific initiation of EC-to-SMC signaling remains elusive. Our previous study demonstrated that endothelial microRNA-126-3p (miR-126-3p) acts as a key intercellular molecule to increase turnover of the recipient SMCs, and that its release is reduced by atheroprotective laminar shear (12 dynes/cm 2 ) to ECs. Here we provide evidence that atherogenic oscillatory shear (0.5 ± 4 dynes/cm 2 ), but not atheroprotective pulsatile shear (12 ± 4 dynes/cm 2 ), increases the endothelial secretion of nonmembrane-bound miR-126-3p and other microRNAs (miRNAs) via the activation of SNAREs, vesicleassociated membrane protein 3 (VAMP3) and synaptosomalassociated protein 23 (SNAP23). Knockdown of VAMP3 and SNAP23 reduces endothelial secretion of miR-126-3p and miR-200a-3p, as well as the proliferation, migration, and suppression of contractile markers in SMCs caused by EC-coculture. Pharmacological intervention of mammalian target of rapamycin complex 1 in ECs blocks endothelial secretion and EC-to-SMC transfer of miR-126-3p through transcriptional inhibition of VAMP3 and SNAP23. Systemic inhibition of VAMP3 and SNAP23 by rapamycin or periadventitial application of the endocytosis inhibitor dynasore ameliorates the disturbed flow-induced neointimal formation, whereas intraluminal overexpression of SNAP23 aggravates it. Our findings demonstrate the flow-pattern-specificity of SNARE activation and its contribution to the miRNA-mediated EC-SMC communication. T he interaction between hemodynamics and vascular endothelium is an important determinant of vascular homeostasis (1). In the straight part of the arteries, endothelial cells (ECs) are exposed to laminar blood flow with high shear stress that protects these parts of the vessels from atherogenesis, whereas in the branches and curvatures, the ECs experiencing disturbed flow with reciprocating and low shear stress stimulate the smooth muscle cells (SMCs) within the tunica media to become proliferative and migratory. The activated SMCs migrate into the intima, where they come into close contact with ECs and undergo phenotypic changes to lead to atherosclerosis (2). We recently demonstrated that vascular ECs repress expressions of forkhead box O3, B-cell lymphoma 2, and insulin receptor substrate 1 in the adjacent SMCs by producing microRNA-126-3p (miR-126-3p), and hence induce SMC turnover, and that the application of atheroprotective laminar shear (LS) at 12 dynes/cm 2 to ECs inhibits this paracrine effect (3). Although extracellular microRNAs (miRNAs) have been shown to convey messages from donor cells to recipient cells, how fluid shear stress regulates endothelial miRNA secretion remains to be elucidated.Emerging evidence has suggested that extracellular miRNAs can serve as not only pu...

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Section: Discussionmentioning

confidence: 99%

VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia

Zhu

Liu

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Mice were fed with a standard laboratory diet and water ad libitum. All animals were maintained in steel cages in a room with a controlled temperature of [20][21][22][23][24][25] C and a 12-h light/ 12-h dark cycle. All animal protocols were approved by the Institutional Animal Care and Use Committee of Chongqing Medical University.…”

Section: Animalsmentioning

confidence: 99%

The SIRT1 inhibitor EX-527 suppresses mTOR activation and alleviates acute lung injury in mice with endotoxiemia

et al. 2017

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It is generally regarded that Sirtuin 1 (SIRT1), a longevity factor in mammals, acts as a negative regulator of inflammation. However, recent studies also found that SIRT1 might be a detrimental factor under certain inflammatory circumstance. In this study, the potential pathophysiological roles and the underlying mechanisms of SIRT1 in a mouse model with endotoxemia-associated acute lung injury were investigated. The results indicated that treatment with the selective SIRT1 inhibitor EX-527 suppressed LPS-induced elevation of TNF-a and IL-6 in plasma. Treatment with EX-527 attenuated LPS-induced histological abnormalities in lung tissue, which was accompanied with decreased myeloperoxidase level and suppressed induction of tissue factor and plasminogen activator inhibitor-1. Treatment with EX-527 also suppressed LPS-induced phosphorylation of eukaryotic translation initiation factor-binding protein 1 (4E-BP1). Co-administration of a mammalian target of rapamycin (mTOR) activator 3-benzyl-5-[(2-nitrophenoxy) methyl]-dihydrofuran-2 (3H)-one (3BDO) abolished the inhibitory effects of EX-527 on 4E-BP1 phosphorylation. Meanwhile, the inhibitory effects of EX-527 on IL-6 induction and the beneficial effects of EX-527 on lung injury were partially reversed by 3BDO. This study suggests that selective inhibition of SIRT1 by EX-527 might alleviate endotoxemia-associated acute lung injury partially via suppression of mTOR, which implies that SIRT1 selective inhibitors might have potential value for the pharmacological intervention of inflammatory lung injury.

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“…WIP1 regulates autophagy via ATM and mTOR, which indicates that this protein may serve a protective role in advanced AS; inactivation of mTOR may therefore provide a novel therapeutic option in the treatment of AS (22). Other recent studies have investigated the effect of small molecular weight compounds and proteins on AS, including 3BDO, microtubule-associated protein 1 light chain 3 beta (MAP1LC3B) and lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) (38). 3BDO activation of mTOR serves to protect endothelial cells and to inhibit the development of AS.…”

Section: Autophagy In Asmentioning

confidence: 99%

“…The 3BDO-induced inhibition of autophagy is mediated by oxLDL in endothelial cells, and decreased ATG expression and autophagy activity in apoE -/-mice. Conversely, 3BDO barely impacts upon mTOR signaling in macrophages and smooth muscle cells, and therefore 3BDO may selectively protect endothelial cells, promoting atherosclerotic plaque stability via the mTOR pathway (38). MAP1LC3B serves a critical role in limiting the development of AS.…”

Section: Autophagy In Asmentioning

confidence: 99%

Role of autophagy in advanced atherosclerosis

Zhu

Fan

Zhang

et al. 2017

Molecular Medicine Reports

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Abstract. Atherosclerosis (AS) remains the leading cause for global cardiovascular disease morbidity and mortality, and a major cause of cardiopathy, myocardial infarction and peripheral vascular diseases. Macrophages serve a critical role in atherosclerotic plaque stabilization and rupture, and the selective removal of macrophages may be beneficial in improving plaque stability. Autophagy is a process of self-feeding, during which cytoplasmic proteins or organelles are packaged into vesicles and fused with the lysosome to form an autophagosome. The newly formed autophagosome can degrade internalized proteins, and this process may be used to serve the metabolic and self-renewal requirements of the cell. Autophagy serves an important role in maintaining cell homeostasis and promoting cell survival, and therefore an imbalance in autophagy is closely associated with multiple diseases. Contents1. Introduction 2. The molecular mechanism of autophagy 3. Autophagy in the vascular system 4. Autophagy in AS 5. Conclusions IntroductionAutophagy is a process of cellular repair and survival, during which cytoplasmic components are sequestered into double-membrane vesicles. Previous research has revealed that autophagy is stimulated in advanced atherosclerotic plaques by oxidized lipids, inflammation and metabolic stress (1). Autophagy is beneficial in promoting cellular recovery in adverse environments; it is also valuable in inhibiting apoptosis. In advanced atherosclerosis (AS), macrophage apoptosis, together with defective phagocytic clearance of the apoptotic cells, promotes plaque necrosis, which results in acute atherothrombotic cardiovascular events (2). Basal autophagy is beneficial in early AS, however a detrimental effect is observed in advanced AS plaques (3); autophagy is capable of protecting cells from oxidative stress via the degradation of damaged intracellular material; however, excessively stimulated autophagic activity may result in significant destruction of the cytosol (1). The latter scenario leads to programmed cell death and may cause vascular endothelial cell (VEC) death, which results in plaque destabilization. Endothelial injury or death represents a predominant mechanism of acute clinical events, due to the promotion of lesional thromboses (4). Furthermore, insufficient autophagic activity also reduces free cholesterol and apolipoprotein A-I (5), and this decreases the amount of high-density lipoprotein. Insufficient and excessive autophagy of VECs are therefore both injurious, and the regulation of autophagic homeostasis may be important in the treatment of AS. The molecular mechanism of autophagyWhen Ashford and Porter (6) perfused rat livers with glucagon, they discovered a large increase in the number of cellular lysosomes. This phenomenon of self-feeding was referred to as autophagy. This process involves the packaging of cytoplasmic proteins or organelles into vesicles, followed by lysosomal fusion, to form an autophagic lysosome; a cellular event which aids in metabolism and in the renewal...

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An activator of mTOR inhibits oxLDL-induced autophagy and apoptosis in vascular endothelial cells and restricts atherosclerosis in apolipoprotein E-/- mice

Cited by 144 publications

References 40 publications

VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia

VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia

The SIRT1 inhibitor EX-527 suppresses mTOR activation and alleviates acute lung injury in mice with endotoxiemia

Role of autophagy in advanced atherosclerosis

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