Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis.

Animals Anticholesteremic Agents / therapeutic use Apolipoprotein A-I / blood Apolipoprotein E3 / genetics Cholesterol Ester Transfer Proteins / antagonists & inhibitors Cholesterol, HDL / blood Cytokines / metabolism Disease Models, Animal Female Gain of Function Mutation Humans Mice Mice, Transgenic Oxazolidinones / therapeutic use Placebo Effect Polymorphism, Single Nucleotide Risk Factors Sepsis / drug therapy Survival Rate
apolipoprotein-AI cholesteryl ester transfer protein high-density lipoprotein sepsis

Journal

Circulation
ISSN: 1524-4539
Titre abrégé: Circulation
Pays: United States
ID NLM: 0147763

Informations de publication

Date de publication:
02 03 2021
Historique:
pubmed: 25 11 2020
medline: 4 1 2022
entrez: 24 11 2020
Statut: ppublish

Résumé

The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis. We examined the effect of a gain-of-function variant in A fixed-effect meta-analysis of all 7 cohorts found that the Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis.

Sections du résumé

BACKGROUND
The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis.
METHODS
We examined the effect of a gain-of-function variant in
RESULTS
A fixed-effect meta-analysis of all 7 cohorts found that the
CONCLUSIONS
Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis.

Identifiants

DOI: 10.1161/CIRCULATIONAHA.120.048568 PMID: 33228395
pubmed: 33228395
doi: 10.1161/CIRCULATIONAHA.120.048568
doi:

Substances chimiques

Anticholesteremic Agents 0
Apolipoprotein A-I 0
Apolipoprotein E3 0
CETP protein, human 0
Cholesterol Ester Transfer Proteins 0
Cholesterol, HDL 0
Cytokines 0
Oxazolidinones 0
anacetrapib P7T269PR6S

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

921-934

Subventions

Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : CIHR
ID : PJT 168838
Pays : Canada

Commentaires et corrections

Type : CommentIn
Type : CommentIn

Auteurs

Mark Trinder (M)

Centre for Heart Lung Innovation (M.T., T.P., L.B., H.J.K., J.A.R., K.R.W., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.
Experimental Medicine Program (M.T., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.

Yanan Wang (Y)

Department of Medicine, Division of Endocrinology (Y.W., L.L.B., P.C.N.R.), Leiden University Medical Center, The Netherlands.

Christian M Madsen (CM)

Department of Clinical Biochemistry (C.M.M., B.G.N., J.A.R.), Copenhagen University Hospital, Denmark.
The Copenhagen General Population Study (C.M.M., B.G.N., A.T.-H.), Copenhagen University Hospital, Denmark.
Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (C.M.M., B.G.N., A.T.-H.).

Tatjana Ponomarev (T)

Centre for Heart Lung Innovation (M.T., T.P., L.B., H.J.K., J.A.R., K.R.W., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.

Lubos Bohunek (L)

Brendan A Daisely (BA)

Department of Microbiology and Immunology, The University of Western Ontario, London, Canada (B.A.D.).

HyeJin Julia Kong (H)

Centre for Heart Lung Innovation (M.T., T.P., L.B., H.J.K., J.A.R., K.R.W., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.

Lisanne L Blauw (LL)

Department of Medicine, Division of Endocrinology (Y.W., L.L.B., P.C.N.R.), Leiden University Medical Center, The Netherlands.

Børge G Nordestgaard (BG)

Department of Clinical Biochemistry (C.M.M., B.G.N., J.A.R.), Copenhagen University Hospital, Denmark.
The Copenhagen General Population Study (C.M.M., B.G.N., A.T.-H.), Copenhagen University Hospital, Denmark.
The Copenhagen City Heart Study, Frederiksberg Hospital (B.G.N., A.T.-H.), Copenhagen University Hospital, Denmark.
Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (C.M.M., B.G.N., A.T.-H.).

Anne Tybjærg-Hansen (A)

The Copenhagen General Population Study (C.M.M., B.G.N., A.T.-H.), Copenhagen University Hospital, Denmark.
Herlev Gentofte Hospital, Department of Clinical Biochemistry, Rigshospitalet (A.T.-H.), Copenhagen University Hospital, Denmark.
The Copenhagen City Heart Study, Frederiksberg Hospital (B.G.N., A.T.-H.), Copenhagen University Hospital, Denmark.
Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (C.M.M., B.G.N., A.T.-H.).

Mark M Wurfel (MM)

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle (M.M.W., K.R.W.).

James A Russell (JA)

Centre for Heart Lung Innovation (M.T., T.P., L.B., H.J.K., J.A.R., K.R.W., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.
Department of Clinical Biochemistry (C.M.M., B.G.N., J.A.R.), Copenhagen University Hospital, Denmark.

Keith R Walley (KR)

Centre for Heart Lung Innovation (M.T., T.P., L.B., H.J.K., J.A.R., K.R.W., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle (M.M.W., K.R.W.).

Patrick C N Rensen (PCN)

Department of Medicine, Division of Endocrinology (Y.W., L.L.B., P.C.N.R.), Leiden University Medical Center, The Netherlands.

John H Boyd (JH)

Centre for Heart Lung Innovation (M.T., T.P., L.B., H.J.K., J.A.R., K.R.W., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.
Experimental Medicine Program (M.T., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.
Department of Medicine (J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.

Liam R Brunham (LR)

Centre for Heart Lung Innovation (M.T., T.P., L.B., H.J.K., J.A.R., K.R.W., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.
Experimental Medicine Program (M.T., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.
Department of Medicine (J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Inhibition of Cholesteryl Ester Transfer...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Agents régulateurs du métabolisme des lipides › Hypolipémiants › Anticholestérolémiants › Inhibition of Cholesteryl Ester Transfer...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Lipoprotéines › Apolipoprotéines › Apolipoprotéines A › Apolipoprotéine A-I › Inhibition of Cholesteryl Ester Transfer...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Lipoprotéines › Apolipoprotéines › Apolipoprotéines E › Apolipoprotéine E3 › Inhibition of Cholesteryl Ester Transfer...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Glycoprotéines › Protéines de transfert des esters de cholestérol › Inhibition of Cholesteryl Ester Transfer...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Lipoprotéines › Lipoprotéines HDL › Cholestérol HDL › Inhibition of Cholesteryl Ester Transfer...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Inhibition of Cholesteryl Ester Transfer...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Inhibition of Cholesteryl Ester Transfer...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation gain de fonction › Inhibition of Cholesteryl Ester Transfer...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Inhibition of Cholesteryl Ester Transfer...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Inhibition of Cholesteryl Ester Transfer...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Inhibition of Cholesteryl Ester Transfer...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Oxazoles › Oxazolidinones › Inhibition of Cholesteryl Ester Transfer...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Facteurs épidémiologiques › Modificateur d'effet épidémiologique › Effet placebo › Inhibition of Cholesteryl Ester Transfer...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Inhibition of Cholesteryl Ester Transfer...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Risque › Facteurs de risque › Inhibition of Cholesteryl Ester Transfer...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Inflammation › Sepsie › Inhibition of Cholesteryl Ester Transfer...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Collecte de données › Registre civil › Mortalité › Taux de survie › Inhibition of Cholesteryl Ester Transfer...