Worsening of diet-induced atherosclerosis in a new model of transgenic rabbit expressing the human plasma phospholipid transfer protein.
OBJECTIVE
Plasma phospholipid transfer protein (PLTP) is involved in intravascular lipoprotein metabolism. PLTP is known to act through 2 main mechanisms: by remodeling high-density lipoproteins (HDL) and by increasing apolipoprotein (apo) B-containing lipoproteins. The aim of this study was to generate a new model of human PLTP transgenic (HuPLTPTg) rabbit and to determine whether PLTP expression modulates atherosclerosis in this species that, unlike humans and mice, displays naturally very low PLTP activity.


RESULTS
In HuPLTPTg rabbits, the human PLTP cDNA was placed under the control of the human eF1-α gene promoter, resulting in a widespread tissue expression pattern and in increased plasma PLTP. The HuPLTPTg rabbits showed a significant increase in the cholesterol content of the plasma apoB-containing lipoprotein fractions, with a more severe trait when animals were fed a cholesterol-rich diet. In contrast, HDL cholesterol level was not modified in HuPLTPTg rabbits. Formation of aortic fatty streaks was increased in hypercholesterolemic HuPLTPTg animals as compared with nontransgenic littermates.


CONCLUSIONS
Human PLTP expression in HuPLTPTg rabbit worsens atherosclerosis as a result of increased levels of atherogenic apoB-containing lipoproteins but not of alterations in their antioxidative protection or in cholesterol content of plasma HDL.
Institut National de la Santé et de la Recherche Médicale, Université de Bourgogne, UMR866, Dijon, France.
David
D
Masson
Valérie
V
Deckert
Thomas
T
Gautier
Alexis
A
Klein
Catherine
C
Desrumaux
Céline
C
Viglietta
Jean-Paul
JP
Pais de Barros
Naig
N
Le Guern
Jacques
J
Grober
Jérôme
J
Labbé
Franck
F
Ménétrier
Pierre-Jean
PJ
Ripoll
Mathieu
M
Leroux-Coyau
Geneviève
G
Jolivet
Louis-Marie
LM
Houdebine
Laurent
L
Lagrost
D000818:Animals; D030801:Animals, Genetically Modified; D001018:Aortic Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001055:Apolipoproteins B / Q000097:blood; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000097:blood; D002791:Cholesterol, Dietary / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D004195:Disease Models, Animal; D045325:HCT116 Cells; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications* / Q000378:metabolism; D020648:Peptide Elongation Factor 1 / Q000235:genetics; D049294:Phospholipid Transfer Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011817:Rabbits; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D001055:Apolipoproteins B; D015415:Biomarkers; D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; C493430:PLTP protein, human; D020648:Peptide Elongation Factor 1; D049294:Phospholipid Transfer Proteins; D011994:Recombinant Proteins