Evidence map›Paper›PMID 26333678›Full record

ArticleThe Journal of pathology2016

Local effects of human PCSK9 on the atherosclerotic lesion.

Ilaria Giunzioni, Hagai Tavori, Roman Covarrubias, Amy S Major, Lei Ding, Youmin Zhang, Rachel M DeVay, Liang Hong, Daping Fan, Irene M Predazzi and 3 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of pathology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
91citing papers in PubMed, 3 pooled it
14.5field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

91 citing papers in PubMed, 3 syntheses or guidelines pooled it, 181 citations in OpenAlex.

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31 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors at 5 institutions in 2 countries.

Ilaria GiunzioniKnight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR, USA.
Hagai TavoriKnight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR, USA.
Roman CovarrubiasDepartment of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
Amy S MajorDepartment of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
Lei DingDivision of Cardiovascular Medicine, Atherosclerosis Research Unit, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Youmin ZhangDivision of Cardiovascular Medicine, Atherosclerosis Research Unit, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Rachel M DeVayRinat-Pfizer Inc., South San Francisco, CA, USA.
Liang HongRinat-Pfizer Inc., South San Francisco, CA, USA.
Daping FanUniversity of South Carolina School of Medicine, Columbia, SC, USA.
Irene M PredazziKnight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR, USA.
Shirya RashidDepartment of Pharmacology, Dalhousie University, Halifax, Nova Scotia, and Saint John, New Brunswick, Canada.
MacRae F LintonDivision of Cardiovascular Medicine, Atherosclerosis Research Unit, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Sergio FazioKnight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR, USA.
Vanderbilt University Medical Center · USOregon Health & Science University · USPfizer (United States) · USSaint John Regional Hospital · CAUniversity of South Carolina · US

Funding

Training In Cardiovascular ResearchT32HL007411 · NHLBI · VANDERBILT UNIVERSITY · PI BECKMAN, JOSHUA A · 1985 to 2020
$7.2M
FUNCTIONAL HIERARCHY OF REMNANT LIPOPROTEIN RECEPTORSR01HL057986 · NHLBI · VANDERBILT UNIVERSITY · PI FAZIO, SERGIO · 1998 to 2016
$6.2M
Functional and structural correlates of PCSK9 association with lipoproteinsR01HL132985 · NHLBI · OREGON HEALTH & SCIENCE UNIVERSITY · PI PAMIR, NATHALIE · 2016 to 2024
$4.2M
PCSK9, Lipoprotein receptors, and AtherosclerosisR01HL106845 · NHLBI · VANDERBILT UNIVERSITY · PI FAZIO, SERGIO · 2011 to 2014
$2.0M
NHLBI NIH HHS R01 HL057986NHLBI NIH HHS R01 HL106845NHLBI NIH HHS R01-HL106845NHLBI NIH HHS R01 HL132985NHLBI NIH HHS T32 HL007411
6 · The paper itself

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes atherosclerosis by increasing low-density lipoprotein (LDL) cholesterol levels through degradation of hepatic LDL receptor (LDLR). Studies have described the systemic effects of PCSK9 on atherosclerosis, but whether PCSK9 has local and direct effects on the plaque is unknown. To study the local effect of human PCSK9 (hPCSK9) on atherosclerotic lesion composition, independently of changes in serum cholesterol levels, we generated chimeric mice expressing hPCSK9 exclusively from macrophages, using marrow from hPCSK9 transgenic (hPCSK9tg) mice transplanted into apoE(-/-) and LDLR(-/-) mice, which were then placed on a high-fat diet (HFD) for 8 weeks. We further characterized the effect of hPCSK9 expression on the inflammatory responses in the spleen and by mouse peritoneal macrophages (MPM) in vitro. We found that MPMs from transgenic mice express both murine (m) Pcsk9 and hPCSK9 and that the latter reduces macrophage LDLR and LRP1 surface levels. We detected hPCSK9 in the serum of mice transplanted with hPCSK9tg marrow, but did not influence lipid levels or atherosclerotic lesion size. However, marrow-derived PCSK9 progressively accumulated in lesions of apoE(-/-) recipient mice, while increasing the infiltration of Ly6C(hi) inflammatory monocytes by 32% compared with controls. Expression of hPCSK9 also increased CD11b- and Ly6C(hi) -positive cell numbers in spleens of apoE(-/-) mice. In vitro, expression of hPCSK9 in LPS-stimulated macrophages increased mRNA levels of the pro-inflammatory markers Tnf and Il1b (40% and 45%, respectively) and suppressed those of the anti-inflammatory markers Il10 and Arg1 (30% and 44%, respectively). All PCSK9 effects were LDLR-dependent, as PCSK9 protein was not detected in lesions of LDLR(-/-) recipient mice and did not affect macrophage or splenocyte inflammation. In conclusion, PCSK9 directly increases atherosclerotic lesion inflammation in an LDLR-dependent but cholesterol-independent mechanism, suggesting that therapeutic PCSK9 inhibition may have vascular benefits secondary to LDL reduction.

Indexed as

AnimalsAtherosclerosisDisease Models, AnimalFlow CytometryFluorescent Antibody TechniqueHumansImmunohistochemistryImmunoprecipitationMacrophages, PeritonealMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicProprotein Convertase 9Proprotein ConvertasesReceptors, LDLPCSK9 protein, humanProprotein Convertase 9Proprotein ConvertasesReceptors, LDLSerine Endopeptidasesatherosclerotic lesioninflammationLDLRmacrophagesmouse modelsPCSK9

Identifiers

PMID26333678
PMCPMC5346023
OpenAlexW2135256854

What OpenQuestion holds

Texttitle and abstract
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.