OLDER PLASMA-LIPOPROTEINS ARE MORE SUSCEPTIBLE TO OXIDATION - A LINKING MECHANISM FOR THE LIPID AND OXIDATION THEORIES OF ATHEROSCLEROTIC CARDIOVASCULAR-DISEASE

Increases in plasma cholesterol are associated with progressive increases in the risk of atherosclerotic cardiovascular disease, In humans plasma cholesterol is contained primarily in apolipoprotein B-based low density lipoprotein (LDL). Cells stop making the high-affinity receptor responsible for LDL removal as they become cholesterol replete; this slows removal of LDL from plasma and elevates plasma LDL. As a result of this delayed uptake, hypercholesterolemic individuals not only have more LDL but have significantly older LDL. Oxidative modification of LDL enhances their atherogenicity. This study sought to determine whether increased time spent in circulation, or aging, by lipoprotein particles altered their susceptibility to oxidative modification, Controlled synchronous production of distinctive apolipoprotein B lipoproteins (yolk-specific very low density lipoproteins; VLDLy) with a single estrogen injection into young turkeys was used to model LDL aging in vivo. VLDLy remained in circulation for at least 10 days, Susceptibility to oxidation in vitro was highly dependent on lipoprotein age in vivo. Oxidation, measured as hexanal release from n-6 fatty acids in VLDLy: increased from 13.3 +/- 5.5 nmol of 2-day-old VLDLy per mi, to 108 +/- 17 nmol of 7-day-old VLDLy per mi, Oxidative instability was not due to tocopherol depletion or conversion to a more unsaturated fatty acid composition, These findings establish mathematically describable linkages between the variables of LDL concentration and LDL oxidation. The proposed mathematical models suggest a unified investigative approach to determine the mechanisms for acceleration of atherosclerotic cardiovascular disease risk as plasma cholesterol rises.