p38 Mitogen-activated Protein Kinase (MAPK) Promotes Cholesterol Ester Accumulation in Macrophages through Inhibition of Macroautophagy

Mei, Shuang; Gu, Haihua; Ward, Adam R.; Yang, Xuefeng; Guo, Haijian; He, Kongwang; Liu, Zhenqi; Cao, Wenhong

doi:10.1074/jbc.m111.333575

Cited by 57 publications

(61 citation statements)

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“…In agreement with the present findings, LOX-1 has been reported to be involved in OxLDL-induced oxidative DNA damage in endothelial cells (23). Activation of MAPKs is implicated in the development of atherosclerosis (6). It has been documented that MAPK-mediated signaling pathways are involved in Chlamydia pneumoniae-induced macrophage-derived foam cell formation (24).…”

Section: Discussionsupporting

confidence: 88%

“…The proatherogenic activity of ROS is mediated through activation of numerous signaling pathways, including mitogen-activated protein kinases (MAPKs) (5). p38 MAPK has been implicated in the development of atherosclerosis via promotion of cholesterol ester accumulation in macrophages and foam cell formation (6). Despite extensive studies on the role of ROS in atherosclerosis (3)(4)(5), relatively little is known about the molecular mechanisms underlying the regulation of ROS production.…”

Section: Introductionmentioning

confidence: 99%

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LOX-1 is implicated in oxidized low-density lipoprotein-induced oxidative stress of macrophages in atherosclerosis

Yang

Bian

Zhang

et al. 2015

Molecular Medicine Reports

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Abstract. Induction of oxidative stress has a causal role in atherosclerosis. The aim of the present study was to examine the role of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in oxidized low-density lipoprotein (OxLDL)-induced oxidative stress in atherosclerosis. Small interfering RNA (siRNA) technology was employed to decrease the expression of LOX-1 in mouse RAW264.7 macrophages and the effects of LOX-1 silencing on OxLDL-induced reactive oxygen species (ROS) generation and NADPH oxidase (NOX) expression were investigated. The in vivo effects of reducing LOX-1 were also examined in a mouse model (ApoE-/-) of high-fat diet-induced atherosclerosis. Compared with the control cells, OxLDL exposure led to a significant (P<0.05) increase in the intracellular levels of malondialdehyde and ROS and a significant decrease in the activity of superoxide dismutase. Delivery of LOX-1-targeting siRNA significantly (P<0.05) reversed the alterations in oxidative stress parameters induced by OxLDL. LOX-1 silencing downregulated the expression of NOX2, Rac1, p47phox and p22phox and impaired the activation of mitogen-activated protein kinases in OxLDL-treated cells. Adenoviral delivery of LOX-1 siRNA caused a significant increase in the size of the fibrous cap and a decrease in the macrophage content in lesions, compared with the control mice. Western blot analysis demonstrated that the protein expression levels of NOX1, Rac1, p47phox and p22phox in aortic lesions were significantly lower in the LOX-1 siRNA group than in the control group. LOX-1 is implicated in OxLDL-induced oxidative stress of macrophages in atherosclerosis, which in part, involves the regulation of NADPH oxidases.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

LOX-1 is implicated in oxidized low-density lipoprotein-induced oxidative stress of macrophages in atherosclerosis

Yang

Bian

Zhang

et al. 2015

Molecular Medicine Reports

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“…***, P Ͻ 0.001; **, P Ͻ 0.01; *, P Ͻ 0.05. of the unfolded protein response (UPR). But in advanced atherosclerosis, a deficiency of ACAT activity results in further cholesterol accumulation and induction of macrophage apoptosis by ER stress (49,50).…”

Section: Discussionmentioning

confidence: 99%

Liposomal Cholesterol Delivery Activates the Macrophage Innate Immune Arm To Facilitate Intracellular Leishmania donovani Killing

et al. 2014

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Leishmania donovani causes visceral leishmaniasis (VL) by infecting the monocyte/macrophage lineage and residing inside specialized structures known as parasitophorous vacuoles. The protozoan parasite has adopted several means of escaping the host immune response, with one of the major methods being deactivation of host macrophages. Previous reports highlight dampened macrophage signaling, defective antigen presentation due to increased membrane fluidity, and the downregulation of several genes associated with L. donovani infection. We have reported previously that the defective antigen presentation in infected hamsters could be corrected by a single injection of a cholesterol-containing liposome. Here we show that cholesterol in the form of a liposomal formulation can stimulate the innate immune arm and reactivate macrophage function. Augmented levels of reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI), along with proinflammatory cytokines such as tumor necrosis factor alpha (TNF-␣) and interleukin 6 (IL-6), corroborate intracellular parasite killing. Cholesterol incorporation kinetics is favored in infected macrophages more than in normal macrophages. Such an enhanced cholesterol uptake is associated with preferential apoptosis of infected macrophages in an endoplasmic reticulum (ER) stress-dependent manner. All these events are coupled with mitogen-activated protein (MAP) kinase activation, while inhibition of such pathways resulted in increased parasite loads. Hence, liposomal cholesterol is a potential facilitator of the macrophage effector function in favor of the host, independently of the T-cell arm.

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“…Autophagy is a catabolic pathway for the bulk turnover of long-lived proteins and organelles via lysosomal degradation. Basal autophagy is a survival mechanism safeguarding vascular cells against oxidative injury, metabolic stress and inflammation (9,10); it is protective against EC injury and was observed in atherosclerotic plaques (11)(12)(13)(14)(15). Degradation of autophagolysosomal content is impaired in CATL(-/-) mice (16).…”

Section: Discussionmentioning

confidence: 99%

Cathepsin L stimulates autophagy and inhibits apoptosis of ox-LDL-induced endothelial cells: Potential role in atherosclerosis

Wei

Jia

Liu

et al. 2012

International Journal of Molecular Medicine

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Abstract. The activation of endothelial cells by oxidized low-density lipoprotein (ox-LDL) with subsequent increases in endothelial permeability occurs in the early stage of atherosclerosis. Cathepsin L (CATL) is one of the cysteine proteases and has been implicated in advanced atherosclerotic lesions and plaque instability. This study aimed to explore the role of CATL in ox-LDL-induced early atherosclerotic events and to delineate the underlying mechanism. Results showed that ox-LDL upregulated CATL protein levels and activation in human umbilical vein endothelial cells (ECs) in a concentration-dependent manner and stimulated EC autophagy and apoptosis and increased EC monolayer permeability. Concomitantly, VE-cadherin expression was decreased. When ECs were pretreated with a CATL inhibitor, ox-LDL-induced autophagy was inhibited while apoptosis was further increased. In addition, the VE-cadherin protein level was increased, and the EC monolayer permeability was reduced. Taken together, the present study showed that the upregulated expression and activation of CATL induced by ox-LDL, increased EC autophagy and antagonized EC apoptosis, which partly neutralized the effect of increased EC monolayer permeability mediated by the downregulation of VE-cadherin. Thus, the proatherogenic effect of CATL was partly neutralized by inducing autophagy and inhibiting apoptosis in early stages of atherosclerosis. IntroductionAn elevated level of oxidized low-density lipoprotein (ox-LDL) is one of the major risk factors for atherosclerosis and plays a major role in vascular endothelial dysfunction. The vascular endothelium acts as a selective barrier, regulating the exchange of macromolecules between blood and the underlying tissues (1). The elevated permeability of the endothelium is the first event in the cascade of processes leading to atherosclerotic lesion formation, which leads to lipid infiltration and accumulation within the arterial wall. Three potential pathways regulate endothelial permeability: namely the transcellular pathway, by which blood components pass through the cell; the paracellular pathway, by which the components cross the endothelial barrier through intercellular cell-cell junctions; and the leaky junction pathway, by which components across the endothelium through the gap due to cells undergoing mitosis or apoptosis (2).Cathepsins belong to the papain family of cysteine proteases, which degrade elastin and collagen. Cathepsin L (CATL) is one of the potent mammalian collagenases and elastases and was found to be upregulated in the arteries of apolipoprotein E-null mice fed a Western diet (3). Inhibition of CATL was able to reduce expression of the adhesion molecule αVβ3 integrin, disrupting secretion of the proangiogenic factors fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) (4). Recently, Mahmoud et al (5) discovered that increased levels of CATL mRNA and protein induced by peroxisome proliferator-activated receptor γ (PPARγ) activation, stimulated apoptosis and inhibited...

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p38 Mitogen-activated Protein Kinase (MAPK) Promotes Cholesterol Ester Accumulation in Macrophages through Inhibition of Macroautophagy

Cited by 57 publications

References 50 publications

LOX-1 is implicated in oxidized low-density lipoprotein-induced oxidative stress of macrophages in atherosclerosis

LOX-1 is implicated in oxidized low-density lipoprotein-induced oxidative stress of macrophages in atherosclerosis

Liposomal Cholesterol Delivery Activates the Macrophage Innate Immune Arm To Facilitate Intracellular Leishmania donovani Killing

Cathepsin L stimulates autophagy and inhibits apoptosis of ox-LDL-induced endothelial cells: Potential role in atherosclerosis

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