Platelet factor 4 binds to low-density lipoprotein receptors and disrupts the endocytic itinerary, resulting in retention of low-density lipoprotein on the cell surface

Sachais, Bruce S.; Kuo, Alice; Nassar, Taher; Morgan, Jeanelle; Karikó, Katalin; Williams, Kevin Jon; Feldman, Michael D.; Aviram, Michael; Shah, Neelima; Jarett, Leonard; Poncz, Mortimer; Cines, Douglas B.; Higazi, Abd Al‐Roof

doi:10.1182/blood.v99.10.3613

Cited by 90 publications

(90 citation statements)

References 57 publications

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“…PF4 actsasachemoattractant formonocytespromoting their differentiation into macrophages (4). Furthermore, PF4 mayd irectly promote atherosclerosis by the inhibitionofLDL catabolism, whichismediated in part by competing for binding to the LDLr eceptor,b yp romoting interactions with cell-associatedc hondroitin sulfate proteoglycans and by disrupting the normal endocytic trafficking of LDL/ LDL-Rcomplexes (5). In addition, PF4markedlyenhances the esterification and uptakeofoxidized LDL by macrophages (6).…”

Section: Platelet Secretion Andgeneration Of Cytokinesmentioning

confidence: 99%

Platelet-vessel wall interactions in atherosclerotic disease

Langer¹,

Gawaz²

2008

Thromb Haemost

195

132

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SummaryDuring the prolonged course of atherosclerotic disease,platelets areofcentral importanceastheycontribute to the initiation of the disease,toi ts progressiona nd acutee xacerbation but also providep otentialr egenerativem echanisms. Platelets secrete chemokinesa nd cytokinest hatm ediatev ascular inflammation andare in turn activated by substances released from cells of the vascularwall.These interactions represent positive andnegative feedback loops, whichincaseofdysregulationmay lead to development andp rogression of disease.Furthermore, platelet adhesion to the endothelium is critical forthe initiation of atherosclerotic lesion formation in vivo.Evenp rior to endotheliald enudation, plateletadhesion governed by disturbedflowatpredilection sites foratherosclerosisinduces recruitment of proatheKeywords Atherothrombosis, plateletphysiology, stemcells rosclerotic cells andrelease of proinflammatory mediators from allinvolved cell types.Finally, the pathogenetic role of platelets for late atheroclerotic eventsincluding plaque rupture,microembolism or spasms withint he microcirculationi sw elle stablished. However, increasing evidence indicatesthatplatelets mediateon the other hand potential regenerativemechanisms. Platelets recruit circulating progenitor cells to sites of vasculari njury. Furthermore,theyinfluencetheir biological activity andmaturation. Therefore,platelets contribute at allstages of vasculardiseaseby interfering with highlyd ynamic processes. Understanding interactions of plateletswith othercirculatingcells andt he vascular wall is aprerequisite to understand cardiovascular disease andto identify potentialtherapeutic targets.

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Section: Platelet Secretion Andgeneration Of Cytokinesmentioning

confidence: 99%

Platelet-vessel wall interactions in atherosclerotic disease

Langer¹,

Gawaz²

2008

Thromb Haemost

195

132

View full text Add to dashboard Cite

show abstract

“…PF4 induces the differentiation of monocytes into macrophages that upregulate both, toll-like receptors (TLRs) involved in macrophage activation and scavenger receptors (SRs) (11). PF4 directly contributes to proatherogenic actions by promoting retention of lipoproteins (12). PF4 also interacts directly with oxidised low-density lipoprotein (oxLDL) leading to an induction of endothelial cell activation and dysfunction, macrophage foam cell formation, and VSMC migration and proliferation (13).…”

mentioning

confidence: 99%

Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD

Müller¹,

Chatterjee²,

Rath³

et al. 2015

Thromb Haemost

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SummaryPlatelets play a pivotal role in chronic inflammation leading to progression of atherosclerosis and acute coronary events. Recent discoveries on novel mechanisms and platelet-dependent inflammatory targets underpin the role of platelets to maintain a chronic inflammatory condition in cardiovascular disease. There is strong and clinically relevant crosslink between chronic inflammation and platelet activation. Antiplatelet therapy is a cornerstone in the prevention and treatment of acute cardiovascular events. The benefit of antiplatelet agents has mainly been attributed to their direct anti-aggregatory impact. Some anti-inflammatory off-target effects have also been described. However, it is unclear whether these effects are secondary due to inhibition of platelet activation or are caused by direct distinct mechanisms interfering with inflammatory pathways. This article will highlight novel platelet associated targets that contribute to inflammation in cardiovascular disease and elucidate mechanisms by which currently available antiplatelet agents evolve anti-inflammatory capacities, in particular by carving out the differential mechanisms directly or indirectly affecting platelet mediated inflammation. It will further illustrate the prognostic impact of antiplatelet therapies by reducing inflammatory marker release in recent cardiovascular trials.

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“…17 Experimental evidence also suggests that Platelet Factor 4, the protein product of PF4, binds cell surface LDL receptors, preventing serum LDL from entering cells. 18 We also found regions on chromosomes 1 and 19 associated with LDL and a region on chromosome 16 associated with HDL. We calculated the distance between each association that we found and the closest significant SNP in a previous analysis and a previous metaanalysis of the phenotypes (Table 3).…”

Section: Comparison Of Single-snp Tests and Haplotype Cluster Testsmentioning

confidence: 69%

Genome-wide haplotypic testing in a Finnish cohort identifies a novel association with low-density lipoprotein cholesterol

Zhang

Browning

2014

Eur J Hum Genet

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We performed genome-wide tests for association between haplotype clusters and each of 9 metabolic traits in a cohort of 5402 Northern Finnish individuals genotyped for 330 000 single-nucleotide polymorphisms. The metabolic traits were body mass index, C-reactive protein, diastolic blood pressure, glucose, high-density lipoprotein (HDL), insulin, low-density lipoprotein (LDL), systolic blood pressure, and triglycerides. Haplotype clusters were determined using Beagle. There were LDL-associated clusters in the chromosome 4q13.3-q21.1 region containing the albumin (ALB) and platelet factor 4 (PF4) genes. This region has not been associated with LDL in previous genome-wide association studies. The most significant haplotype cluster in this region was associated with 0.488 mmol/l higher LDL (95% CI: 0.361-0.615 mmol/l, P-value: 6.4 Â 10 À14 ). We also observed three previously reported associations: Chromosome 16q13 with HDL, chromosome 1p32. INTRODUCTIONThe identification of genetic factors that influence quantitative traits such as low-density lipoprotein (LDL) has clinical importance. For example, higher LDL levels are associated with increased risk of cardiovascular health disease, and the discovery of the association between PCSK9 mutations and LDL led to the development of PCSK9 inhibitors as a novel class of LDL-reducing drugs. 1 Notably, in the cohort study that found the LDL-associated PCSK9 mutations, each mutation was present in fewer than 2% of study individuals. 2 The standard single-SNP analysis commonly employed in genome-wide association studies (GWAS) has low power for detecting such low frequency causal variants. By employing haplotypic analysis in combination with single-SNP analysis, we can improve power above that of single-SNP analysis alone for detecting causal variants with low minor allele frequency. 3 The standard approach for association analysis of genome-wide single-nucleotide polymorphism (SNP) array data in population samples is to test each SNP individually for association with the trait. This approach can have high power to detect an ungenotyped causal variant when the causal variant is common and correlated with one or more genotyped variants on the array. However, the single-SNP approach has lower power to detect low frequency ungenotyped causal variants. 3 To improve power for low frequency variants, one could impute them and test for association with the trait, but imputation of low frequency variants suffers from poor accuracy. 4 Moreover, variants that are unique to the population of interest

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Platelet factor 4 binds to low-density lipoprotein receptors and disrupts the endocytic itinerary, resulting in retention of low-density lipoprotein on the cell surface

Cited by 90 publications

References 57 publications

Platelet-vessel wall interactions in atherosclerotic disease

Platelet-vessel wall interactions in atherosclerotic disease

Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD

Genome-wide haplotypic testing in a Finnish cohort identifies a novel association with low-density lipoprotein cholesterol

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