Mildly oxidized LDL induces an increased apolipoprotein J/paraoxonase ratio.
We have examined the effects of mildly oxidized LDL and atherosclerosis on the levels of two proteins associated with HDL; apolipoprotein J (apoJ), and paraoxonase (PON). On an atherogenic diet, PON activity decreased by 52%, and apoJ levels increased 2.8-fold in fatty streak susceptible mice, C57BL/6J (BL/6), but not in fatty streak resistant mice, C3H/HeJ (C3H). Plasma PON activity was also significantly decreased, and apoJ levels were markedly increased in apolipoprotein E knockout mice on the chow diet, resulting in a 9.2-fold increase in the apoJ/PON ratio as compared to controls. Furthermore, a dramatic increase in the apoJ/PON ratio (over 100-fold) was observed in LDL receptor knockout mice when they were fed a 0.15%-cholesterol-enriched diet. Injection of mildly oxidized LDL (but not native LDL) into BL/6 mice (but not in C3H mice) on a chow diet resulted in a 59% decrease in PON activity (P < 0.01) and a 3.6-fold increase in apoJ levels (P < 0.01). When an acute phase reaction was induced in rabbits, or the rabbits were placed on an atherogenic diet, hepatic mRNA for apoJ was increased by 2.7-fold and 2.8-fold, respectively. Treatment of HepG2 cells in culture with mildly oxidized LDL (but not native LDL) resulted in reduced mRNA levels for PON (3.0-fold decrease) and increased mRNA levels for apoJ (2.0-fold increase). In normolipidemic patients with angiographically documented coronary artery disease who did not have diabetes and were not on lipid-lowering medication (n = 14), the total cholesterol/HDL cholesterol ratio was 3.1+/-0.9 as compared to 2.9+/-0.4 in the controls (n = 19). This difference was not statistically significant. In contrast, the apoJ/PON ratio was 3.0+/-0.4 in the patients compared to 0.72+/-0.2 in the controls (P < 0.009). In a subset of these normolipidemic patients (n = 5), the PON activity was low (48+/-6.6 versus 98+/-17 U/ml for controls; P < 0.009), despite similar normal HDL levels, and the HDL from these patients failed to protect against LDL oxidation in co-cultures of human artery wall cells. We conclude that: (a) mildly oxidized LDL can induce an increased apoJ/PON ratio, and (b) the apoJ/PON ratio may prove to be a better predictor of atherosclerosis than the total cholesterol/HDL cholesterol ratio.
Navab
M
M
Department of Medicine, School of Medicine, College of Letters and Sciences, University of California, Los Angeles 90095, USA. mnavab@medicine.medsch.ucla.edu
Hama-Levy
S
S
Van Lenten
B J
BJ
Fonarow
G C
GC
Cardinez
C J
CJ
Castellani
L W
LW
Brennan
M L
ML
Lusis
A J
AJ
Fogelman
A M
AM
La Du
B N
BN
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism; D043303:Aryldialkylphosphatase; D001483:Base Sequence; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D051152:Clusterin; D004036:Diet, Atherogenic; D004950:Esterases / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones; D015345:Oligonucleotide Probes / Q000235:genetics; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism
D001057:Apolipoproteins E; C495242:CLU protein, human; C495243:Clu protein, mouse; D051152:Clusterin; D006023:Glycoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D018832:Molecular Chaperones; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D004950:Esterases; D043303:Aryldialkylphosphatase