Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice

Que, Xuchu; Hung, Ming-Yow; Yeang, Calvin; Gonen, Ayelet; Prohaska, Thomas A.; Sun, Xiaoli; Diehl, Cody J.; Määttä, Antti; Gaddis, Dalia E.; Bowden, Karen; Pattison, Jennifer; MacDonald, Jeffrey G.; Ylä‐Herttuala, Seppo; Mellon, Pamela L.; Hedrick, Catherine C.; Ley, Klaus; Miller, Yury I.; Glass, Christopher K.; Peterson, Kirk L.; Binder, Christoph J.; Tsimikas, Sotirios; Witztum, Joseph L.

doi:10.1038/s41586-018-0198-8

Cited by 380 publications

(353 citation statements)

References 41 publications

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“…Additional work will be required to determine the causal genes responsible for the association between these novel loci and AD. Finally, given evidence that phospholipids are proinflammatory [35], future work should evaluate whether LDL, HDL TG, or TC influence AD risk through inflammation or other mediator variables.…”

Section: Discussionmentioning

confidence: 99%

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

et al. 2018

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Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer’s disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10−9), MINK1 (chromosome 17, meta-p = 1.98 × 10−7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10−7 and closest gene = MYBPC3, meta-p = 5.62 × 10−8). In a large ‘AD-by-proxy’ cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.

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Section: Discussionmentioning

confidence: 99%

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

et al. 2018

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“…48 In this context, Lp-PLA2 might exert anti-inflammatory effects, as PAF and its analogs and truncated oxLDL potentially induce inflammatory responses. [148][149][150] However, increasing evidence suggests that Lp-PLA2 seems to be a promoter in the development and progression of inflammation, primarily due to its proinflammatory products, lysoPC and oxNEFA, as previously described. 11,13 In addition, the binding of Lp- but are almost absent in stable lesions.…”

Section: Biological Functions and Disease Implicationsmentioning

confidence: 77%

“…Lp‐PLA2 was shown to have the ability to degrade the PAF and its analogs and the oxLDL species containing short, oxidized, and/or truncated sn ‐2 chains, without any threat to the integrity of phospholipid components within cellular membranes and lipoproteins . In this context, Lp‐PLA2 might exert anti‐inflammatory effects, as PAF and its analogs and truncated oxLDL potentially induce inflammatory responses . However, increasing evidence suggests that Lp‐PLA2 seems to be a promoter in the development and progression of inflammation, primarily due to its proinflammatory products, lysoPC and oxNEFA, as previously described .…”

Section: Biological Functions and Disease Implicationsmentioning

confidence: 99%

Lipoprotein‐associated phospholipase A2: The story continues

Huang

Wang

Shen

2019

Medicinal Research Reviews

109

140

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Inflammation is thought to play an important role in the pathogenesis of vascular diseases. Lipoprotein‐associated phospholipase A2 (Lp‐PLA2) mediates vascular inflammation through the regulation of lipid metabolism in blood, thus, it has been extensively investigated to identify its role in vascular inflammation‐related diseases, mainly atherosclerosis. Although darapladib, the most advanced Lp‐PLA2 inhibitor, failed to meet the primary endpoints of two large phase III trials in atherosclerosis patients cotreated with standard medical care, the research on Lp‐PLA2 has not been terminated. Novel pathogenic, epidemiologic, genetic, and crystallographic studies regarding Lp‐PLA2 have been reported recently, while novel inhibitors were identified through a fragment‐based lead discovery strategy. More strikingly, recent clinical and preclinical studies revealed that Lp‐PLA2 inhibition showed promising therapeutic effects in diabetic macular edema and Alzheimer's disease. In this review, we not only summarized the knowledge of Lp‐PLA2 established in the past decades but also emphasized new findings in recent years. We hope this review could be valuable for helping researchers acquire a much deeper insight into the nature of Lp‐PLA2, identify more potent and selective Lp‐PLA2 inhibitors, and discover the potential indications of Lp‐PLA2 inhibitors.

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“…High plasma concentrations of the fragment (20–30 μg ml −1 ) were achieved that were sufficient to inhibit proinflammatory effects of OxPCs in vitro and in vivo. Furthermore, transgenic mice were protected from development of atheroscleosis, calcification of aortic valve, and liver lipodystrophy in LDL receptor‐knockout mice fed high cholesterol diet . Another evidence for pathogenic role of OxPC in vivo was obtained in an ischemia‐reperfusion model where overexpression of the E06 antibody fragment protected animals and reduced myocardial infarct size .…”

Section: Structure and Biological Effects Of Oxplsmentioning

confidence: 96%

“…Several recent publications provided strong additional support for the pathological importance of OxPLs in vivo. In order to test pathological role of OxPLs, transgenic mice were developed on the low‐density lipoprotein (LDL) receptor‐deficient background expressing a variable region of an antibody E06 in liver cells and monocytes . This antibody binds oxidized phosphatidylcholine and neutralizes its proinflammatory activity.…”

Section: Structure and Biological Effects Of Oxplsmentioning

confidence: 99%

OxPLs‐Masking/Degradation Immune Assay: An “All‐Included” Analysis of Mechanisms Detoxifying Oxidized Phospholipids

Philippova¹,

Oskolkova

Bochkov

2019

Euro J Lipid Sci & Tech

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The manuscript discusses the use of circulating oxidized phospholipids (OxPLs) as potential disease biomarkers. Blood levels of OxPLs have been previously demonstrated to be strongly associated with cardiovascular disease. These data were obtained using an immune assay based on monoclonal antibody E06 which detects oxidized phosphatidylcholine. The impact of other classes of OxPLs on disease progression is not known. It is postulated that 1) other classes of OxPLs may contribute to cardiovascular disease and 2) both the absolute concentrations of OxPLs and the activity of detoxifying mechanisms are essential factors linking OxPLs with disease progression. Among such mechanisms is opsonization of OxPLs by endogenous antibodies and other plasma proteins. Furthermore, plasma contains enzymes degrading OxPLs. Experimental data from this study show that highly diluted blood plasma significantly reduces (“masks”) binding of E06, as well as another anti‐OxPL monoclonal antibody that recognizes oxidized phosphatidylethanolamine, to OxLDL. Potentially, sequestration or degradation of OxPLs by plasma proteins, antibodies or enzymes can ameliorate pathogenic effects of OxPLs, thus preventing disease onset. Based on these considerations, it is hypothesized that analysis of blood levels of “masking/degrading” proteins may provide important additional information complementary to the E06‐based assay and therefore improve its diagnostic value. Practical Applications: The manuscript discusses application of antibodies against OxPLs for their analysis as potential disease biomarkers. Plates are coated with OxLDL, blocked and incubated with either control buffer or plasma, which contains proteins and enzymes binding or degrading OxPLs present on OxLDL. Then the amount of remaining OxPLs is determined using monoclonal antibodies detecting OxPCs or OxPEs. The difference in signal intensities between the buffer‐ and plasma‐treated wells represents the activity of OxPLs‐masking/degradation.

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Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice

Cited by 380 publications

References 41 publications

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

Lipoprotein‐associated phospholipase A2: The story continues

OxPLs‐Masking/Degradation Immune Assay: An “All‐Included” Analysis of Mechanisms Detoxifying Oxidized Phospholipids

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