Older plasma lipoproteins are more susceptible to oxidation: A linking mechanism for the lipid and oxidation theories of atherosclerotic cardiovascular disease

R. L. Walzem, S. Watkins, E. N. Frankel, R. J. Hansen, J. B. German

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

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 ml, to 108 ± 17 nmol of 7-day-old VLDLy per ml. 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.

Original languageEnglish (US)
Pages (from-to)7460-7464
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number16
DOIs
StatePublished - Aug 1 1995

Fingerprint

LDL Lipoproteins
Lipoproteins
Cardiovascular Diseases
Lipids
Cholesterol
Apolipoproteins B
Tocopherols
VLDL Lipoproteins
LDL Receptors
Unsaturated Fatty Acids
Estrogens
Theoretical Models
Fatty Acids
Injections

Keywords

  • animal model
  • gene expression
  • mathematical model

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Older plasma lipoproteins are more susceptible to oxidation : A linking mechanism for the lipid and oxidation theories of atherosclerotic cardiovascular disease. / Walzem, R. L.; Watkins, S.; Frankel, E. N.; Hansen, R. J.; German, J. B.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 92, No. 16, 01.08.1995, p. 7460-7464.

Research output: Contribution to journalArticle

@article{9bf5ed24ca5041b8926da02df2d0a9ae,
title = "Older plasma lipoproteins are more susceptible to oxidation: A linking mechanism for the lipid and oxidation theories of atherosclerotic cardiovascular disease",
abstract = "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 ml, to 108 ± 17 nmol of 7-day-old VLDLy per ml. 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.",
keywords = "animal model, gene expression, mathematical model",
author = "Walzem, {R. L.} and S. Watkins and Frankel, {E. N.} and Hansen, {R. J.} and German, {J. B.}",
year = "1995",
month = "8",
day = "1",
doi = "10.1073/pnas.92.16.7460",
language = "English (US)",
volume = "92",
pages = "7460--7464",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "16",

}

TY - JOUR

T1 - Older plasma lipoproteins are more susceptible to oxidation

T2 - A linking mechanism for the lipid and oxidation theories of atherosclerotic cardiovascular disease

AU - Walzem, R. L.

AU - Watkins, S.

AU - Frankel, E. N.

AU - Hansen, R. J.

AU - German, J. B.

PY - 1995/8/1

Y1 - 1995/8/1

N2 - 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 ml, to 108 ± 17 nmol of 7-day-old VLDLy per ml. 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.

AB - 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 ml, to 108 ± 17 nmol of 7-day-old VLDLy per ml. 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.

KW - animal model

KW - gene expression

KW - mathematical model

UR - http://www.scopus.com/inward/record.url?scp=0029153929&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029153929&partnerID=8YFLogxK

U2 - 10.1073/pnas.92.16.7460

DO - 10.1073/pnas.92.16.7460

M3 - Article

C2 - 7638213

AN - SCOPUS:0029153929

VL - 92

SP - 7460

EP - 7464

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 16

ER -