Published Online
on June 30, 2003

A more recent version of this article appeared on July 22, 2003

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Submitted on February 4, 2003
Revised on April 14, 2003
Accepted on April 18, 2003

Cell-Associated and Extracellular Phospholipid Transfer Protein in Human Coronary Atherosclerosis

Kevin D. O'Brien MD, Simona Vuletic MD, Thomas O. McDonald MS, Gertrud Wolfbauer PhD, Katherine Lewis PhD, An-Yue Tu PhD, Santica Marcovina PhD, Thomas N. Wight PhD, Alan Chait MD, and John J. Albers PhD^*

From the Divisions of Cardiology (K.D.O., T.O.M.) and Metabolism, Endocrinology and Nutrition (S.V., G.W., K.L., A.-Y.T., S.M., A.C., J.J.A.), Department of Medicine, University of Washington, and Hope Heart Institute (T.N.W.), Seattle, Wash.

^* To whom correspondence should be addressed. E-mail: jja{at}u.washington.edu.

Background--Phospholipid transfer protein (PLTP) plays an important role in HDL particle metabolism and may modulate hepatic secretion of apolipoprotein B-containing lipoproteins. However, whether PLTP might participate directly in human atherosclerotic lesion formation is unknown.

Methods and Results--The cellular and extracellular distributions of PLTP were determined in normal and atherosclerotic human coronary lesions with a monoclonal antibody to human PLTP. Cell types (smooth muscle cells [SMCs] or macrophages), apolipoproteins (apoA-I, apoB, and apoE), and extracellular matrix proteoglycans (biglycan and versican) were identified on adjacent sections with monospecific antibodies. Minimal extracellular PLTP was detected in nonatherosclerotic coronary arteries, but extracellular and cellular PLTP immunostaining was widespread in atherosclerotic lesions. PLTP was detected in foam cell SMCs and in foam cell macrophages, which suggests that cellular cholesterol accumulation might increase PLTP expression in both cell types. This was confirmed by in vitro studies demonstrating that cholesterol loading of macrophages leads to 2- to 3-fold increases in PLTP steady-state mRNA levels, protein expression, and activity. PLTP also was detected in an extracellular distribution, colocalizing with apoA-I, apoB, apoE, and the vascular proteoglycan biglycan. In gel mobility shift assays, both active and inactive recombinant PLTP markedly increased HDL binding to biglycan, which suggests that PLTP may mediate lipoprotein binding to proteoglycans independent of its phospholipid transfer activity.

Conclusions--PLTP is present in human atherosclerotic lesions, and its distribution suggests roles for PLTP in both cellular cholesterol metabolism and lipoprotein retention on extracellular matrix.

Key words: lipoproteins • apolipoproteins • atherosclerosis • lipids • cells

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