on July 10, 2003
Published online before print July 10, 2003, doi: 10.1161/01.ATV.0000085841.55248.13
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Submitted on May 21, 2003
Accepted on June 26, 2003
Increased Atherosclerotic Lesions and Lipoprotein Oxidizability in Apolipoprotein E-Null Mice Overexpressing Plasma Phospholipid Transfer Protein
Xiao Ping Yang ;
From the Department of Anatomy and Cell Biology, State University of New York, Downstate Medical Center (X.P.Y., D.Y., R.J.L., J.C., X.C.J.), Brooklyn, NY; Department of Molecular Genetics and Biochemistry, University of Pittsburgh (C.Q., J.L., X.X.), Pittsburgh, Pa; and INSERM U498, Faculté de Médecine (M.S., L.L.), Dijon, France.
* To whom correspondence should be addressed. E-mail: xjiang{at}downstate.edu.
Objective--Plasma phospholipid transfer protein (PLTP) is involved in the metabolism of HDLs and apolipoprotein B (apoB)-containing lipoproteins. Atherosclerosis susceptibility is decreased in mice with PLTP deficiency that is associated with decreased liver production of apoB-containing lipoproteins and increase in their antioxidant. To investigate additionally the effect of PLTP on the development of atherosclerosis, we overexpressed PLTP in mice.
Methods and Results--PLTP was overexpressed in apoE knockout mice using an adenovirus-associated virus (AAV)-mediated system. Plasma PLTP activity was 1.3- to 2-fold higher in mice injected with AAV-PLTP than in mice injected with control AAV-GFP, and PLTP levels were sustained during the experiment period (4 months). We show that 2-fold increased PLTP activity results in (1) a decrease in HDL cholesterol, HDL phospholipid, and apoAI levels; (2) a decrease in vitamin E contents in total plasma and in individual lipoprotein fractions; (3) an increase in lipoprotein oxidizability as assessed by copper-induced formation of conjugated dienes; (4) an increase in autoantibodies against oxidized apoB-containing particles; and (5) an increase in atherosclerosis lesions in proximal aorta.
Conclusions--These observations indicate that elevated plasma PLTP levels constitute a novel, long-term risk factor for atherosclerosis.
Key words: phospholipid transfer protein • apoB-containing lipoproteins • oxidation • high-density lipoprotein • atherosclerosis
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