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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:e63.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Oxidation of Apolipoprotein B-100 in Circulating LDL Is Related to LDL Residence Time

In Vivo Insights From Stable-Isotope Studies

Jens Pietzsch; Peter Lattke; Ulrich Julius

From the Institute and Polyclinic of Clinical Metabolic Research (J.P., U.J.) and the Institute of Clinical Chemistry and Laboratory Medicine (P.L.), Medical Faculty, Technical University Dresden, Dresden, Germany.

Correspondence to Dr Jens Pietzsch, Institute and Polyclinic of Clinical Metabolic Research, Medical Faculty ‘Carl Gustav Carus,’ Technical University, Fetscherstrasse 74, D-01307 Dresden, Germany. E-mail julius{at}rcs.urz.tu-dresden.de

Abstract—5-Hydroxy-2-aminovaleric acid (HAVA) has been suggested to be a specific marker of oxidation of apolipoprotein (apo) B-100 proline (Pro) and arginine (Arg) side-chain residues in low density lipoprotein (LDL) in vitro. Here we describe the application of sensitive mass spectrometric techniques to the characterization of Pro/Arg-modified apoB-100 in LDL₁ (S_f 7 to 12) and LDL₂ (S_f 0 to 7) in vivo. We studied 7 subjects with familial defective apoB-100 (FDB) and 8 normolipidemic controls. In FDB subjects, the presence of a mutant apoB-100 (FDB_3500Q) in LDL markedly reduced its affinity for the LDL receptor, leading to increased residence times (RTs) of LDL₁ (65±21 versus 32±12 hours, P<0.005) and LDL₂ (230±40 versus 53±7 hours, P<0.001) when compared with controls, as determined by stable-isotope turnover studies. LDL₁ HAVA content was not different between the groups (FDB, 0.004±0.001 mol/mol apoB-100 versus controls, 0.003±0.001 mol/mol apoB-100, P=0.200). LDL₂ HAVA content was higher in FDB subjects (0.374±0.088 versus 0.013±0.002 mol/mol apoB-100, P<0.001). In both groups, LDL₂ HAVA was positively associated with LDL₂ RT (FDB, r=0.893, P=0.003; controls, r=0.976, P=0.000) and negatively correlated with LDL₂ -tocopherol content (FDB, r=-0.929, P=0.003; controls, r=-0.903, P=0.002). No significant correlations could be found between LDL₁ HAVA, LDL₁ RT, and -tocopherol, respectively. The low LDL₁ HAVA content observed in both FDB and control groups was thought to be due to the relatively lower RT as well as the higher -tocopherol content of these lipoproteins. In contrast, LDL₂ seemed to be strongly prone to direct oxidation of apoB-100 in vivo. The longer these particles linger in the circulation, the more apoB-100 Pro/Arg residues become modified.

Key Words: familial defective apolipoprotein B-100 • lipoproteins • residence time • oxidation • atherosclerosis