MILDLY OXIDIZED LDL INDUCES AN INCREASED APOLIPOPROTEIN-J PARAOXONASERATIO

We have examined the effects of mildly oxidized LDL and atherosclerosi s on the levels of two proteins associated with HDL; apolipoprotein J (apoJ), and paraoxonase (PON). On an atherogenic diet, PON activity de creased by 52%, and apoJ levels increased 2.8-fold in fatty streak sus ceptible 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/PO N ratio as compared to controls. Furthermore, a dramatic increase in t he apoJ/PON ratio (over 100-fold) was observed in LDL receptor knockou t 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 i n 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 place d on an atherogenic diet, hepatic mRNA for apoJ was increased by 2.7-f old and 2.8-fold, respectively. Treatment of HepG2 cells in culture wi th mildly oxidized LDL (but not native LDL) resulted in reduced mRNA l evels for PON (3.0-fold decrease) and increased mRNA levels for apoJ ( 2.0-fold increase). In normolipidemic patients with angiographically d ocumented coronary artery disease who did not have diabetes and were n ot on lipid-lowering medication (n = 14), the total cholesterol/HDL ch olesterol 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 contr ast, 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 normolipidemi c 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 t he total cholesterol/HDL cholesterol ratio.