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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:1580-1587.)
© 1996 American Heart Association, Inc.

Articles

Selective Resistance of LDL Core Lipids to Iron-Mediated Oxidation

Implications for the Biological Properties of Iron-Oxidized LDL

Diane L. Tribble; Berbie M. Chu; Gerri A. Levine; Ronald M. Krauss; Elaine L. Gong

Department of Molecular and Nuclear Medicine, Life Science Division, Lawrence Berkeley National Laboratory, University of California, Berkeley.

Correspondence to Diane L. Tribble, Lawrence Berkeley National Laboratory, Donner Laboratory, Room 465, University of California, Berkeley, CA 94720.

Although the nature and consequences of oxidative changes in the chemical constituents of low density lipoproteins (LDLs) have been extensively examined, the physical dynamics of LDL oxidation and the influence of physical organization on the biological effects of oxidized LDLs have remained relatively unexplored. To address these issues, in the present studies we monitored surface- and core-specific peroxidative stress relative to temporal changes in conjugated dienes (CDs), particle charge (an index of oxidative protein modification), and LDL-macrophage interactions. Peroxidative stress in LDL surface and core compartments was evaluated with the site-specific, oxidation-labile fluorescent probes parinaric acid (PnA) and PnA cholesteryl ester (PnCE), respectively. When oxidation was initiated by Cu²⁺, oxidative loss of the core probe (PnCE) closely followed that of the surface probe (PnA), as indicated by the time to 50% probe depletion (t_1/2; 15.5±7.8 and 30.4±12 minutes for PnA and PnCE, respectively). Both probes were more resistant in LDL exposed to Fe³⁺ (t_1/2, 53.2±8.1 and 346.7±155.4 minutes), although core probe resistance was much greater with this oxidant (PnCE t_1/2/PnA t_1/2, 5.8 vs 2.0 for Cu²⁺). Despite differences in the rate and extent of oxidative changes in Cu²⁺- versus Fe³⁺-exposed LDLs, PnCE loss occurred in close correspondence with CD formation and appeared to precede changes in particle charge under both conditions. Exposure of LDLs to hemin, a lipophilic Fe³⁺-containing porphyrin that becomes incorporated into the LDL particle, resulted in rapid loss of PnCE and simultaneous changes in particle charge, even at concentrations that yielded increases in CDs and thiobarbituric acid–reactive substances similar to those obtained with free Fe³⁺. These results suggest that oxidation of the LDL hydrophobic core occurs in conjunction with accelerated formation of CDs and may be essential for LDL protein modification. In accordance with the known effects of oxidative protein modifications on LDL receptor recognition, exposure of LDLs to Cu²⁺ and hemin but not Fe³⁺ produced particles that were readily processed by macrophages. Thus, the physical site of oxidative injury appears to be a critical determinant of the chemical and biological properties of LDLs, particularly when oxidized by Fe³⁺.

Key Words: lipid peroxidation • parinaric acid • copper • iron • hemin

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