Open AccessModification of Type III VLDL, Their Remnants, and VLDL From ApoE-Knockout Mice by p -Hydroxyphenylacetaldehyde, a Product of Myeloperoxidase Activity, Causes Marked Cholesteryl Ester Accumulation in Macrophages
Author(s) -
Stewart C. Whitman,
Stanley L. Hazen,
David B. Miller,
Robert A. Hegele,
Jay W. Heinecke,
Murray W. Huff
Publication year - 1999
Publication title -
arteriosclerosis, thrombosis, and vascular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.007
H-Index - 270
eISSN - 1524-4636
pISSN - 1079-5642
DOI - 10.1161/01.atv.19.5.1238
Subject(s) - myeloperoxidase , very low density lipoprotein , apolipoprotein e , chemistry , cholesteryl ester , knockout mouse , macrophage , biochemistry , microbiology and biotechnology , cholesterol , inflammation , lipoprotein , medicine , biology , immunology , in vitro , gene , disease
—Very low density lipoproteins (VLDLs) from apolipoprotein (apo) E2/E2 subjects with type III hyperlipoproteinemia, VLDL remnants, and VLDL from apoE-knockout (EKO) mice are taken up poorly by macrophages. The present study examined whether VLDL modification by the reactive aldehydep -hydroxyphenylacetaldehyde (pHA) enhances cholesteryl ester (CE) accumulation by J774A.1 macrophages. pHA is the major product derived from the oxidation ofl -tyrosine by myeloperoxidase and is a component of human atherosclerotic lesions. Incubation of J774A.1 cells with native type III VLDL, their remnants, and EKO-VLDL increased cellular CE by only 3-, 5-, and 5-fold, respectively, compared with controls. In striking contrast, cells exposed to VLDL modified by purified pHA (pHA-VLDL) exhibited marked increases in cellular CE of 38-, 47-, and 35-fold, respectively (P ≤0.0001). Addition of the lipoprotein lipase inhibitor tetrahydrolipstatin decreased cellular CE accumulation induced by the 3 pHA-modified VLDL preparations by 73%, 59%, and 73%, respectively. Addition of the acyl coenzyme A:cholesterol acyltransferase inhibitor DuP 128 to cells incubated with the pHA-modified lipoproteins decreased cellular CE by 100%, 82%, and 95%, respectively, but had no effect on cellular triglycerides. To examine whether the type A scavenger receptors (SR-As) mediated the uptake of pHA-VLDL, incubations were performed in the presence of polyinosine (poly I), a polynucleotide known to block binding to SR-As (types I and II), or in cells preincubated with interferon-γ (IFN-γ), a cytokine known to decrease expression of SR-A type I. Coincubation of pHA-VLDL with poly I reduced cellular CE by only 38%, 44%, and 49%, respectively, whereas coincubation with IFN-γ reduced CE by only 18%, 27%, and 65%, respectively. In marked contrast to pHA-VLDL, both poly I and IFN-γ inhibited, by>95%, CE accumulation induced by copper-oxidized VLDL. These results demonstrate a novel mechanism for the conversion of type III VLDLs, their remnants, and EKO-VLDL into atherogenic particles and suggest that macrophage uptake of pHA-VLDL (1) requires catalytically active lipoprotein lipase, (2) involves acyl coenzyme A:cholesterol acyltransferase–mediated cholesterol esterification, and (3) involves pathways distinct from the SR-A.