The role of the low-density lipoprotein receptor in transport and metabolism of LDL through the wall of normal rabbit aorta in vivo. Estimation of model parameters from optimally designed dual-tracer experiments

The author measured degradation rate constants for low density lipoproteiin (LDL) and methylated LDL (not recognized by the LDL-receptor) in the intima and media of the rabbit aorta. Experiments involved intravenous injection of 125I-LDL and tyramine-cellobiose-LDL (131I-TC-LDL), or their methylated counterparts. Labeled protein fragments of TC-LDL become permanently deposited intracellularly upon degradation. Transmural concentration data were described by a diffusive mass transport model including degradation in the media and intima. The tissue data consisted of instantaneous (125I-LDL) and accumulating transmural signals (131I-TC-LDL + 131I-TC-protein fragments). The author assumed on intimal thickness, ΔX, of 0.5 microns, a fluid space fraction in tissue of 0.1 for LDL, and a common degradation rate constant for intima and media. He estimated an apparent first order degradation rate constant in media (K), luminal permeability (P1), and other transport parameters. At 24 hours, the average K was 0.419 ± 0.172 x 10-4 (sec-1) for methylated LDL (n = 4), and 0.350 ± 0.086 x 10-4 (sec-1) for non-methylated (n = 3). These values were insensitive to the value chosen for intimal thickness. They indicate an absence of receptor-mediated degradation of LDL in the normal rabbit aortic media in vivo. These data suggest that 25% of the labeled LDL transported into the aortic wall is degraded by the intima within 24 hours of injection. Simulations predicted that the steady state percentage of degradation in the intima is 34% of total aortic degradation