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Elevated Expression of Phospholipid Transfer Protein in Bone Marrow Derived Cells Causes Atherosclerosis

BACKGROUND: Phospholipid transfer protein (PLTP) is expressed by various cell types. In plasma, it is associated with high density lipoproteins (HDL). Elevated levels of PLTP in transgenic mice result in decreased HDL and increased atherosclerosis. PLTP is present in human atherosclerotic lesions, w...

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Autores principales: van Haperen, Rien, Samyn, Hannelore, Moerland, Matthijs, van Gent, Teus, Peeters, Marian, Grosveld, Frank, van Tol, Arie, de Crom, Rini
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386265/
https://www.ncbi.nlm.nih.gov/pubmed/18509527
http://dx.doi.org/10.1371/journal.pone.0002255
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author van Haperen, Rien
Samyn, Hannelore
Moerland, Matthijs
van Gent, Teus
Peeters, Marian
Grosveld, Frank
van Tol, Arie
de Crom, Rini
author_facet van Haperen, Rien
Samyn, Hannelore
Moerland, Matthijs
van Gent, Teus
Peeters, Marian
Grosveld, Frank
van Tol, Arie
de Crom, Rini
author_sort van Haperen, Rien
collection PubMed
description BACKGROUND: Phospholipid transfer protein (PLTP) is expressed by various cell types. In plasma, it is associated with high density lipoproteins (HDL). Elevated levels of PLTP in transgenic mice result in decreased HDL and increased atherosclerosis. PLTP is present in human atherosclerotic lesions, where it seems to be macrophage derived. The aim of the present study is to evaluate the atherogenic potential of macrophage derived PLTP. METHODS AND FINDINGS: Here we show that macrophages from human PLTP transgenic mice secrete active PLTP. Subsequently, we performed bone marrow transplantations using either wild type mice (PLTPwt/wt), hemizygous PLTP transgenic mice (huPLTPtg/wt) or homozygous PLTP transgenic mice (huPLTPtg/tg) as donors and low density lipoprotein receptor deficient mice (LDLR−/−) as acceptors, in order to establish the role of PLTP expressed by bone marrow derived cells in diet-induced atherogenesis. Atherosclerosis was increased in the huPLTPtg/wt→LDLR−/− mice (2.3-fold) and even further in the huPLTPtg/tg→LDLR−/− mice (4.5-fold) compared with the control PLTPwt/wt→LDLR−/− mice (both P<0.001). Plasma PLTP activity levels and non-HDL cholesterol were increased and HDL cholesterol decreased compared with controls (all P<0.01). PLTP was present in atherosclerotic plaques in the mice as demonstrated by immunohistochemistry and appears to co-localize with macrophages. Isolated macrophages from PLTP transgenic mice do not show differences in cholesterol efflux or in cytokine production. Lipopolysaccharide activation of macrophages results in increased production of PLTP. This effect was strongly amplified in PLTP transgenic macrophages. CONCLUSIONS: We conclude that PLTP expression by bone marrow derived cells results in atherogenic effects on plasma lipids, increased PLTP activity, high local PLTP protein levels in the atherosclerotic lesions and increased atherosclerotic lesion size.
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spelling pubmed-23862652008-05-28 Elevated Expression of Phospholipid Transfer Protein in Bone Marrow Derived Cells Causes Atherosclerosis van Haperen, Rien Samyn, Hannelore Moerland, Matthijs van Gent, Teus Peeters, Marian Grosveld, Frank van Tol, Arie de Crom, Rini PLoS One Research Article BACKGROUND: Phospholipid transfer protein (PLTP) is expressed by various cell types. In plasma, it is associated with high density lipoproteins (HDL). Elevated levels of PLTP in transgenic mice result in decreased HDL and increased atherosclerosis. PLTP is present in human atherosclerotic lesions, where it seems to be macrophage derived. The aim of the present study is to evaluate the atherogenic potential of macrophage derived PLTP. METHODS AND FINDINGS: Here we show that macrophages from human PLTP transgenic mice secrete active PLTP. Subsequently, we performed bone marrow transplantations using either wild type mice (PLTPwt/wt), hemizygous PLTP transgenic mice (huPLTPtg/wt) or homozygous PLTP transgenic mice (huPLTPtg/tg) as donors and low density lipoprotein receptor deficient mice (LDLR−/−) as acceptors, in order to establish the role of PLTP expressed by bone marrow derived cells in diet-induced atherogenesis. Atherosclerosis was increased in the huPLTPtg/wt→LDLR−/− mice (2.3-fold) and even further in the huPLTPtg/tg→LDLR−/− mice (4.5-fold) compared with the control PLTPwt/wt→LDLR−/− mice (both P<0.001). Plasma PLTP activity levels and non-HDL cholesterol were increased and HDL cholesterol decreased compared with controls (all P<0.01). PLTP was present in atherosclerotic plaques in the mice as demonstrated by immunohistochemistry and appears to co-localize with macrophages. Isolated macrophages from PLTP transgenic mice do not show differences in cholesterol efflux or in cytokine production. Lipopolysaccharide activation of macrophages results in increased production of PLTP. This effect was strongly amplified in PLTP transgenic macrophages. CONCLUSIONS: We conclude that PLTP expression by bone marrow derived cells results in atherogenic effects on plasma lipids, increased PLTP activity, high local PLTP protein levels in the atherosclerotic lesions and increased atherosclerotic lesion size. Public Library of Science 2008-05-28 /pmc/articles/PMC2386265/ /pubmed/18509527 http://dx.doi.org/10.1371/journal.pone.0002255 Text en van Haperen et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
van Haperen, Rien
Samyn, Hannelore
Moerland, Matthijs
van Gent, Teus
Peeters, Marian
Grosveld, Frank
van Tol, Arie
de Crom, Rini
Elevated Expression of Phospholipid Transfer Protein in Bone Marrow Derived Cells Causes Atherosclerosis
title Elevated Expression of Phospholipid Transfer Protein in Bone Marrow Derived Cells Causes Atherosclerosis
title_full Elevated Expression of Phospholipid Transfer Protein in Bone Marrow Derived Cells Causes Atherosclerosis
title_fullStr Elevated Expression of Phospholipid Transfer Protein in Bone Marrow Derived Cells Causes Atherosclerosis
title_full_unstemmed Elevated Expression of Phospholipid Transfer Protein in Bone Marrow Derived Cells Causes Atherosclerosis
title_short Elevated Expression of Phospholipid Transfer Protein in Bone Marrow Derived Cells Causes Atherosclerosis
title_sort elevated expression of phospholipid transfer protein in bone marrow derived cells causes atherosclerosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386265/
https://www.ncbi.nlm.nih.gov/pubmed/18509527
http://dx.doi.org/10.1371/journal.pone.0002255
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