PLA
            <sub>2</sub>
            -V

Öörni, Katariina; Kovanen, Petri T.

doi:10.1161/01.atv.0000258412.58289.ee

Cited by 10 publications

(4 citation statements)

References 27 publications

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“…The retained lipoproteins become modified by arterial-wall enzymes and oxidants, 6 , 7 tend to aggregate, 8 and aggregated lipoprotein-derived particles are found both in human and in experimentally induced atherosclerotic lesions in animal models. 9–12 The intimal processes triggering aggregation of LDL particles have been proposed to include lipid peroxidation and proteolytic and lipolytic digestion of LDL by local enzymes, such as the mast cell chymase having chymotrypsin-like activity, 13 the group V secretory phospholipase A 2 (PLA 2 ), 14 which is produced by macrophages, as well as the secretory sphingomyelinase (SMase), which is released by macrophages and endothelial cells. 15 Aggregation enhances the binding of lipoproteins to the arterial extracellular matrix, 8 and their large size makes egress back across the endothelium nearly impossible.…”

Section: Introductionmentioning

confidence: 99%

“… 7 Moreover, aggregated LDL induces the formation of foam cells, a hallmark of lesions at all stages of atherogenesis. 14 , 16 , 17 Indeed, the development of an atherosclerotic lesion involves a series of maladaptive responses of innate and adaptive immune cells to the retained, modified, and aggregated lipoprotein-derived material. 18 , 19 …”

Section: Introductionmentioning

confidence: 99%

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Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths

Ruuth

Nguyen

Vihervaara

et al. 2018

European Heart Journal

144

157

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AimsLow-density lipoprotein (LDL) particles cause atherosclerotic cardiovascular disease (ASCVD) through their retention, modification, and accumulation within the arterial intima. High plasma concentrations of LDL drive this disease, but LDL quality may also contribute. Here, we focused on the intrinsic propensity of LDL to aggregate upon modification. We examined whether inter-individual differences in this quality are linked with LDL lipid composition and coronary artery disease (CAD) death, and basic mechanisms for plaque growth and destabilization.Methods and resultsWe developed a novel, reproducible method to assess the susceptibility of LDL particles to aggregate during lipolysis induced ex vivo by human recombinant secretory sphingomyelinase. Among patients with an established CAD, we found that the presence of aggregation-prone LDL was predictive of future cardiovascular deaths, independently of conventional risk factors. Aggregation-prone LDL contained more sphingolipids and less phosphatidylcholines than did aggregation-resistant LDL. Three interventions in animal models to rationally alter LDL composition lowered its susceptibility to aggregate and slowed atherosclerosis. Similar compositional changes induced in humans by PCSK9 inhibition or healthy diet also lowered LDL aggregation susceptibility. Aggregated LDL in vitro activated macrophages and T cells, two key cell types involved in plaque progression and rupture.ConclusionOur results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths

Ruuth

Nguyen

Vihervaara

et al. 2018

European Heart Journal

144

157

View full text Add to dashboard Cite

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“…The current opinion is that plasma levels of enzymes of the sPLA 2 family are positively associated with the pathogenesis of atherosclerosis by various mechanisms, including the generation of atherogenic lipoprotein particles (63) and the activation of several proinflammatory pathways (64). In fact, some physiological functions of sPLA 2 enzymes are unrelated to their lipolytic activity and can be ascribed to the engagement of specific receptors on target cells (65).…”

Section: Apoa-i After Sds-page Separationmentioning

confidence: 99%

Proteolysis of Apolipoprotein A-I by Secretory Phospholipase A2

Cavigiolio¹,

Jayaraman

2014

Journal of Biological Chemistry

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“…To account for these problems, we hypothesised that LDL nonoxidatively modified and aggregated by enzymes, such as sphingomyelinase [16], proteases [17] or secretory phospholipase A 2 enzymes [18], in the extracellular space of atherosclerotic lesions [19] is rapidly endocytosed by macrophages and delivered to lysosomes, where it might be oxidised [20]. In support of this view, we showed that 7 days after taking up mechanically-aggregated (vortexed) LDL, mouse J774 macrophage-like cells and human monocyte-derived macrophages (HMDM) generated ceroid in their lysosomes.…”

Section: Introductionmentioning

confidence: 99%

Cysteamine inhibits lysosomal oxidation of low density lipoprotein in human macrophages and reduces atherosclerosis in mice

et al. 2019

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Background and aimsWe have shown previously that low density lipoprotein (LDL) aggregated by vortexing is internalised by macrophages and oxidised by iron in lysosomes to form the advanced lipid/protein oxidation product ceroid. We have now used sphingomyelinase-aggregated LDL, a more pathophysiological form of aggregated LDL, to study lysosomal oxidation of LDL and its inhibition by antioxidants, including cysteamine (2-aminoethanethiol), which concentrates in lysosomes by several orders of magnitude. We have also investigated the effect of cysteamine on atherosclerosis in mice.MethodsLDL was incubated with sphingomyelinase, which increased its average particle diameter from 26 to 170 nm, and was then incubated for up to 7 days with human monocyte-derived macrophages. LDL receptor-deficient mice were fed a Western diet (19–22 per group) and some given cysteamine in their drinking water at a dose equivalent to that used in cystinosis patients. The extent of atherosclerosis in the aortic root and the rest of the aorta was measured.ResultsConfocal microscopy revealed lipid accumulation in lysosomes in the cultured macrophages. Large amounts of ceroid were produced, which colocalised with the lysosomal marker LAMP2. The antioxidants cysteamine, butylated hydroxytoluene, amifostine and its active metabolite WR-1065, inhibited the production of ceroid. Cysteamine at concentrations well below those expected to be present in lysosomes inhibited the oxidation of LDL by iron ions at lysosomal pH (pH 4.5) for prolonged periods. Finally, we showed that the extent of atherosclerotic lesions in the aortic root and arch of mice was significantly reduced by cysteamine.ConclusionsThese results support our hypothesis that lysosomal oxidation of LDL is important in atherosclerosis and hence antioxidant drugs that concentrate in lysosomes might provide a novel therapy for this disease.

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PLA ₂ -V

Cited by 10 publications

References 27 publications

Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths

Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths

Proteolysis of Apolipoprotein A-I by Secretory Phospholipase A2

Cysteamine inhibits lysosomal oxidation of low density lipoprotein in human macrophages and reduces atherosclerosis in mice

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PLA 2 -V

Cited by 10 publications

References 27 publications

Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths

Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths

Proteolysis of Apolipoprotein A-I by Secretory Phospholipase A2

Cysteamine inhibits lysosomal oxidation of low density lipoprotein in human macrophages and reduces atherosclerosis in mice

Contact Info

Product

Resources

About

PLA ₂ -V