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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

Morris, Evan Daniel
http://rave.ohiolink.edu/etdc/view?acc_num=case1055528562

Abstract Details

1991, Doctor of Philosophy, Case Western Reserve University, Biomedical Engineering.
We measured degradation rate constants for low density lipoprotein (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). We assumed an 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. We 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 × 10-4 (sec-1) for methylated LDL (n = 4), and 0.350 ± 0.086 × 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. A discrepancy was observed between parameter estimates from 4-hour and 24-hour tracer circulations. Parameter estimates from the shorter experiments predicted greater accumulation of labeled degradation products at 24 hours than were measured. This discrepancy could be resolved by introducing a finite leakage rate (Λ = 0.12 hr-1) for labeled TC-fragments from the tissue. Leakage has been detected previously but has otherwise been ignored. A simultaneous estimate of intimal thickness was made possible by constraining the parameter estimates based on the observation that intimal degradation was 40% of total aortic degradation (Carew et al., 1984). We determined a parameter for intimal degradation via the term K Δx (= 0.410 × 10-9 cm/sec) and a luminal permeability (P1 = 1.18 × 10-9 cm/sec). By estimating P1 while allowing both Δx and K to vary, we measured the intimal barrier to transport independent of luminal degradation. Together, these values 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.
Guy Chisolm (Advisor)
382 p.
role low-density lipoprotein receptor transport metabolism LDL wall normal rabbit aorta in vivo. Estimation model parameters optimally designed dual-tracer experiments

Recommended Citations

Citations

  • Morris, E. D. (1991). 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 [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1055528562

    APA Style (7th edition)

  • Morris, Evan. 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. 1991. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1055528562.

    MLA Style (8th edition)

  • Morris, Evan. "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." Doctoral dissertation, Case Western Reserve University, 1991. http://rave.ohiolink.edu/etdc/view?acc_num=case1055528562

    Chicago Manual of Style (17th edition)

case1055528562
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© 1991, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.