IN-VITRO OXIDIZED HDL IS RECOGNIZED BY THE SCAVENGER RECEPTOR OF MACROPHAGES - IMPLICATIONS FOR ITS PROTECTIVE ROLE IN-VIVO

To assess the effects of oxidative modification, human HDL was oxidise d in vitro for 12 h (Ox-HDL12) and 24 h (Ox-HDL24) under similar condi tions to those commonly used for LDL. The procedure resulted in: an in crease in thiobarbituric acid reactive substances but with marginal ch ange in electronegativity; protein denaturation accounting for 16% and 45% loss of immunoreactive apoprotein A-I in the Ox-HDL12 and Ox-HDL2 4 respectively relative to the non-oxidised, native HDL (Nat-HDL); a d ecrease in the polyunsaturated fatty acids of the triglyceride, choles terol ester and phospholipid components of the lipoprotein; an increas e in the proportion of short chain saturated fatty acids while the mon ounsaturated fatty acids remained relatively unchanged. Studies with h uman macrophages demonstrated: a decrease of 16% and 30% in the capaci ty of the Ox-HDL12 and Ox-HDL24 respectively to efflux intracellular f ree cholesterol; I-125-Ox-HDL24 uptake and degradation was directly co mparable with that of I-125-Ac-LDL; the addition of excess unlabelled Ox-HDL24, Ac-LDL, Ox-LDL24 and Nat-HDL resulted in 74%, 67%, 69% and 1 9% displacement of the I-125-Ox-HDL24 respectively; fucoidin and dextr an sulphate displaced I-125-Ox-HDL by 20% and 40% respectively; intrac ellular free and esterified cholesterol was increased 2.5-fold and 4-f old respectively relative to Nat-HDL on incubation with Ox-HDL24. Thes e findings suggest that HDL is susceptible to oxidative modification l eading to recognition by the scavenger receptor of macrophages and sub sequent intracellular cholesterol accumulation. As such, the in vivo p rotective role of HDL in cardiovascular disease can be reversed in tho se circumstances in which HDL, like LDL, undergoes oxidative modificat ion.