Oxidized high-density lipoprotein accelerates atherosclerosis progression by inducing the imbalance between treg and teff in LDLR knockout mice

Ding, Ru; He, Zhiqing; Zhu, Lin; Wu, Feng; zhang, Feng; Zhang, Jiayou; Ren, Yusheng; Fan, Min; Liang, Chun; Wu, Zonggui

doi:10.1111/apm.12362

Cited by 20 publications

(11 citation statements)

References 66 publications

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“…HDL increased the absolute numbers of Tregs in murine models (10). As HDL has also been shown to enhance the survival of endothelial cells in vitro (17), we thus evaluated the effect of HDL on the viability of purified Tregs…”

Section: Hdl Promotes Survival Of Tregs But Not Of Naïve or Memory Tmentioning

confidence: 99%

“…notably preventing atherosclerotic disease or pulmonary hypertension (8,9). This anti-inflammatory property could be at least partially mediated by an effect of HDL on Tregs, as splenic Treg counts in LDL receptor (LDLR) knockout mice increased after intraperitoneal injection of HDL/ ApoA-I (10,11). In addition, we recently showed that Treg frequency positively correlated with HDL-cholesterol (HDL-C) levels in healthy adults treated with statins (12).…”

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confidence: 99%

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High density lipoproteins selectively promote the survival of human regulatory T cells

Rueda

Rodríguez‐Perea

Moreno‐Fernandez

et al. 2017

Journal of Lipid Research

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HDLs appear to affect regulatory T cell (Treg) homeostasis, as suggested by the increased Treg counts in HDL-treated mice and by the positive correlation between Treg frequency and HDL-cholesterol levels in statin-treated healthy adults. However, the underlying mechanisms remain unclear. Herein, we show that HDLs, not LDLs, significantly decreased the apoptosis of human Tregs in vitro, whereas they did not alter naïve or memory CD4 T cell survival. Similarly, oleic acid bound to serum albumin increased Treg survival. Tregs bound and internalized high amounts of HDL compared with other subsets, which might arise from the higher expression of the scavenger receptor class B type I by Tregs; accordingly, blocking this receptor hindered HDL-mediated Treg survival. Mechanistically, we showed that HDL increased Treg ATP concentration and mitochondrial activity, enhancing basal respiration, maximal respiration, and spare respiratory capacity. Blockade of FA oxidation by etoxomir abolished the HDL-mediated enhanced survival and mitochondrial activity. Our findings thus suggest that Tregs can specifically internalize HDLs from their microenvironment and use them as an energy source. Furthermore, a novel implication of our data is that enhanced Treg survival may contribute to HDLs' anti-inflammatory properties.

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Section: Hdl Promotes Survival Of Tregs But Not Of Naïve or Memory Tmentioning

confidence: 99%

mentioning

confidence: 99%

High density lipoproteins selectively promote the survival of human regulatory T cells

Rueda

Rodríguez‐Perea

Moreno‐Fernandez

et al. 2017

Journal of Lipid Research

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“…Ox-HDL has been detected in atherosclerotic plaques (11). It has been reported that ox-HDL exerts a cytotoxic effect on macrophages and accelerates atherosclerosis progression (12,13). However, the precise underlying mechanisms are poorly understood.…”

Section: Cell Culture and Sirna Transfectionmentioning

confidence: 99%

Oxidized high density lipoprotein induces macrophage apoptosis via toll-like receptor 4-dependent CHOP pathway

Yao¹,

Tian²,

Zhao³

et al. 2017

Journal of Lipid Research

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This article is available online at http://www.jlr.org Atherosclerosis, one of the prime causes of heart attack and stroke, has been well known as a lipid-driven inflammatory disease characterized by macrophage accumulation in subendothelial space. Apoptosis of macrophage-derived foam cells, especially in advanced atherosclerotic lesions where phagocytic clearance of dead and dying cells is defective, results in acellular necrotic lesions that are prone to plaque rupture and thrombosis formation, leading to the majority of acute vascular events (1). Thus, deeper understanding of the mechanisms of macrophage apoptosis may pave the way for developing novel therapeutic strategies to effectively prevent atherosclerotic plaque rupture and subsequent clinical complications (2). Oxidized LDL (ox-LDL) has been recognized as a major inducer, promoting foam cell formation and apoptosis in macrophages (3). In contrast, HDL exerts antiatherogenic functions such as promoting reverse cholesterol transport, suppressing inflammation, inhibiting LDL oxidation, and increasing endothelial nitric oxide production (4). However, accumulating evidence suggests that HDL, like LDL, is also susceptible to oxidative modification. Oxidized HDL Abstract Oxidized HDL (ox-HDL), unlike native HDL that exerts antiatherogenic effects, plays a proatherogenic role. However, the underlying mechanisms are not completely understood. This study was designed to explore the inductive effect of ox-HDL on endoplasmic reticulum (ER) stress-CCAAT-enhancer-binding protein homologous protein (CHOP)-mediated macrophage apoptosis and its upstream mechanisms. Our results showed that ox-HDL could be ingested by macrophages, causing intracellular lipid accumulation. As with tunicamycin (an ER stress inducer), ox-HDL induced macrophage apoptosis with concomitant activation of ER stress pathway, including nuclear translocation of activating transcription factor 6, phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2, and upregulation of glucose-regulated protein 78 and CHOP, which were inhibited by 4-phenylbutyric acid (PBA, an ER stress inhibitor) and CHOP gene silencing. Additionally, diphenyleneiodonium (DPI, an oxidative stress inhibitor), probucol (a reactive oxygen species scavenger), and toll-like receptor 4 (TLR4) silencing reduced ox-HDL-induced macrophage apoptosis, oxidative stress, and CHOP upregulation. Moreover, HDL isolated from patients with metabolic syndrome induced macrophage apoptosis, oxidative stress, and CHOP upregulation, which were blocked by PBA and DPI. These data indicate that ox-HDL may activate ER stress-CHOP-induced apoptotic pathway in macrophages via enhanced oxidative stress and that this pathway may be mediated by TLR4.

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“…Limited studies utilizing highly sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS), oxidized phospholipids (oxPLs) contained within Lp(a) have been shown to augment the pro-inflammatory response and promote CVD progression, an effect that was attenuated with inactivation of oxPLs 7 . Additionally, lower oxHDL also had pro-atherosclerotic effects and was accompanied by significant immunological responses 8 .…”

Section: Introductionmentioning

confidence: 99%

Association Between Oxidation-Modified Lipoproteins and Coronary Plaque in Psoriasis

Sorokin

Kotani

Elnabawi

et al. 2018

Circulation Research

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Rationale: Psoriasis (PSO) is a systemic inflammatory skin disease associated with cardiovascular disease (CVD) and lipid dysfunction. However, traditional lipid parameters have limited prognostic value whereas assessing oxidation-modified lipids (OMLs) in this inflammatory driven condition may capture additional risk. Recently, a study showed that PSO was associated with increased lipid rich coronary plaques, therefore, investigating potential relationships with OMLs may speed understanding of increased CVD in PSO. Objective: To understand whether OMLs associate with traditional lipid phenotypes, cardiometabolic disease biomarkers and total coronary plaque, with focus on non-calcified burden (NCB) by CCTA in psoriasis. Methods and Results: PSO subjects and controls (n=252) had profiling for oxidation-modified LDL, HDL, Lp(a), cholesterol efflux capacity (CEC), lipoprotein particle size and number by NMR spectroscopy and paraoxonase (PON1) activity. Blinded CCTA coronary artery disease characterization included total burden (TB), NCB and dense-calcified burden (DCB). Compared to healthy volunteers (HV), PSO subjects were older (mean age=50.1), had increased BMI and HOMA-IR. PSO subjects had increase in oxLp(a), Lp(a) and oxHDL (p<0.05 for all) with significant association of oxLDL (β=0.10, p=0.020) and oxHDL (β=−0.11, p=0.007) with NCB. Moreover, PSO subjects expressed significantly higher PON1 (kU/μl) activity compared to HV (8.55 ± 3.21 vs. 6.24 ± 3.82, p=0.01). Finally, PSO treatment was associated with a reduction in oxHDL (U/ml) (203.79 ± 88.40 vs. 116.36 ± 85.03, p<0.001) and with a concomitant decrease in NCB at one year (1.04 ± 0.44 vs. 0.95 ± 0.32, p=0.03). Conclusions: Traditional lipids did not capture risk of lipid rich plaque as assessed by NCB, whereas assaying oxidation-modification of lipids revealed significant association with oxLDL and oxHDL. The PON-1 activity was increased in PSO suggesting possible compensatory anti-oxidative effect. Psoriasis treatment was associated with a reduction in oxHDL. These findings support performance of larger studies to understand oxidation-modified lipids in inflammatory states.

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Oxidized high-density lipoprotein accelerates atherosclerosis progression by inducing the imbalance between treg and teff in LDLR knockout mice

Cited by 20 publications

References 66 publications

High density lipoproteins selectively promote the survival of human regulatory T cells

High density lipoproteins selectively promote the survival of human regulatory T cells

Oxidized high density lipoprotein induces macrophage apoptosis via toll-like receptor 4-dependent CHOP pathway

Association Between Oxidation-Modified Lipoproteins and Coronary Plaque in Psoriasis

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