Demacker, P.N.M.

Katan, M.B.

Kleinveld, H.A.

Kosmeijer-Schuil, J.G.

Stalenhoef, A.F.H.

VU Research Portal

VU Research PortalIn vivo oxidised cholesterol in atherosclerosisStalenhoef, A.F.H.; Kleinveld, H.A.; Kosmeijer-Schuil, J.G.; Demacker, P.N.M.; Katan,M.B.published inAtherosclerosis1993document versionPublisher's PDF, also known as Version of recordLink to publication in VU Research Portalcitation for published version (APA)Stalenhoef, A. F. H., Kleinveld, H. A., Kosmeijer-Schuil, J. G., Demacker, P. N. M., & Katan, M. B. (1993). In vivooxidised cholesterol in atherosclerosis. Atherosclerosis, 223(98), 113-4.General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.            • Users may download and print one copy of any publication from the public portal for the purpose of private study or research.            • You may not further distribute the material or use it for any profit-making activity or commercial gain            • You may freely distribute the URL identifying the publication in the public portal ?Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.E-mail address:vuresearchportal.ub@vu.nlDownload date: 22. May. 2021Atherosclerosis, 98 (1993) 113- 114 0 1993 Elsevier Scientific Publishers Ireland, Ltd. All rights reserved. 0021-9150/93/$06.00 Printed and Published in Ireland ATHERO 04946 Letter to the Editors 113 In vivo oxidised cholesterol in atherosclerosis Anton F.H. Stalenhoef”, Henne A. Kleinveld”, Truus G. Kosmeijer-Schuilb, Pierre N.M. Demackera and Martijn B. Katanb ‘Department of Medicine, Division of General Internal Medicine, University Hospital Nijmegen and bDepartment of Human Nutrition, Wageningen Agricultural University, Wageningen (The Netherlands) Key words: Oxidized cholesterol; Modified LDL; Atherosclerosis Dear Editors, Evidence has been increasing the last several years that oxidative modification of LDL may play an important role in the pathogenesis of atherosclerosis [1,2]. Further support for the oxi- dative modification hypothesis is provided by the recent report of Salonen et al. [3] who found that the titre of autoantibodies to malondialdehyde- modified LDL was an independent predictor of the progression of carotid atherosclerosis. Although there is little doubt about the specificity of these antibodies to artificially oxidised LDL [4], direct evidence that LDL oxidation actually takes place in vivo is scarce; most research on oxidation of LDL involves oxidisability in vitro. We have measured circulating cholesterol oxidation prod- ucts in WHHL rabbits. Six-month-old rabbits Correspondence to: Dr. A.F.H. Stalenhoef, Department of In- ternal Medicine, University Hospital Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. (mean (& SD.) serum cholesterol 18.3 f 2.3 IIUXlOVl, mean serum triglycerides 3.2 f 0.9 rnmol/l) were fed with either cholesterol-free con- trol chow or chow mixed with the antioxidant pro- bucol in a low dose (10 mg/kg per day). High doses of probucol are known to retard atherogenesis in these animals [5]. One control animal died during the study period. After 6 months of treatment blood was drawn into vacutainer tubes containing EDTA plus 10 mg of reduced glutathione, plasma was prepared immediately and 0.1 mg of the anti- oxidant butylated hydroxytoluene added per ml. This treatment effectively prevents oxidation in vitro: in plasma of 5 normal volunteers we found total oxysterol levels of 1.36 pmol/l at time 0 and 1.32 pmol/l after 6 month of storage at -80°C. Cholesterol oxidation products were determined by a modification of our previously described method [6]. The mean concentration of serum cholesterol was unaffected in the control animals (18.6 f 1.3 114 TABLE 1 PLASMA LEVELS OF OXYSTEROLS (Fmol/l) IN 3 CON- TROL AND 4 PROBUCOL-TREATED WHHL RABBITS (MEAN (S.D.)) Control Probucol P Total oxysterols 9.15 (1.33) 4.64 (0.58) <O.Ol 7a-Hydroxycholesterol 5.04 (0.33) 2.17 (0.64) c 0.001 5,6c+Epoxycholestanol 0.78 (0.44) 0.39 (0.21) NS 7&Hydroxycholesterol 0.69 (0.23) 0.54 (0.09) NS So-Cholestanetriol 0.88 (0.10) 0.55 (0.09) <O.Ol 7-Ketocholesterol 1.41 (0.39) 0.84 (0.11) co.01 25-Hydroxycholesterol 0.35 (0.13) 0.15 (0.02) < 0.05 vs. 19.0 f 1.9 mmol/l), whereas there was a slight decrease in the probucol treated animals (17.7 f 2.4 vs. 14.2 & 1.8 mmol/I). Ingestion of a low dose of probucol caused a 50% difference in the levels of circulating cholesterol oxidation products (oxysterols) (Table 1). This study provides direct evidence that oxidis- ed lipoproteins occur in vivo in the circulation and that administration of low doses of probucol can prevent oxidation to a large extent, explaining its anti-atherogenic effect in WHHL rabbits. References Steinberg, D., Parthasarathy, S., Carew, T.E., Khoo, J.C., and Witztum, J.L., Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity, N. Engl. J. Med., 320 (1989) 915. Witztum, J.L. and Steinberg, D., Role of oxidized low density lipoprotein in atherogenesis, J. Clin. Invest., 88 (1991) 1785. Salonen J.T., Yla-Herttuala, S., Yamamoto, R., Butler, S., Korpela, H., Salonen, R., Nyysdnen, K., Palinski, W. and Witztum J.L., Autoantibody against oxidised LDL and the progression of carotid atherosclerosis, Lancet, 339 (1992) 883. Editorial, Antibodies to oxidised LDL in atherosclerosis, Lancet, 339 (1992) 899. Carew, T.E., Schwenke, D.C. and Steinberg, D., Anti- atherogenic effect of probucol unrelated to its hypocholesterolemic effect: Evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit, Proc. Natl. Acad. Sci. USA, 84 (1987) 7725. van de Bovenkamp P., Kosmeijer-Schuil, T.G. and Katan, M.B., Quantification of oxysterols in Dutch foods: Egg products and mixed diets, Lipids, 23 (1988) 1079. 

English

In vivo oxidised cholesterol in atherosclerosis

DSpace at VU

Atherosclerosis, 98 (1993) 113- 114 
0 1993 Elsevier Scientific Publishers Ireland, Ltd. All rights reserved. 0021-9150/93/$06.00 
Printed and Published in Ireland 
ATHERO 04946 
Letter to the Editors 
113 
In vivo oxidised cholesterol in atherosclerosis 
Anton F.H. Stalenhoef”, Henne A. Kleinveld”, Truus G. Kosmeijer-Schuilb, 
Pierre N.M. Demackera and Martijn B. Katanb 
‘Department of Medicine, Division of General Internal Medicine, University Hospital Nijmegen and bDepartment of Human Nutrition, 
Wageningen Agricultural University, Wageningen (The Netherlands) 
Key words: Oxidized cholesterol; Modified LDL; Atherosclerosis 
Dear Editors, 
Evidence has been increasing the last several 
years that oxidative modification of LDL may 
play an important role in the pathogenesis of 
atherosclerosis [1,2]. Further support for the oxi- 
dative modification hypothesis is provided by the 
recent report of Salonen et al. [3] who found that 
the titre of autoantibodies to malondialdehyde- 
modified LDL was an independent predictor of 
the progression of carotid atherosclerosis. 
Although there is little doubt about the specificity 
of these antibodies to artificially oxidised LDL [4], 
direct evidence that LDL oxidation actually takes 
place in vivo is scarce; most research on oxidation 
of LDL involves oxidisability in vitro. We have 
measured circulating cholesterol oxidation prod- 
ucts in WHHL rabbits. Six-month-old rabbits 
Correspondence to: Dr. A.F.H. Stalenhoef, Department of In- 
ternal Medicine, University Hospital Nijmegen, P.O. Box 9101, 
6500 HB Nijmegen, The Netherlands. 
(mean (& SD.) serum cholesterol 18.3 f 2.3 
IIUXlOVl, mean serum triglycerides 3.2 f 0.9 
rnmol/l) were fed with either cholesterol-free con- 
trol chow or chow mixed with the antioxidant pro- 
bucol in a low dose (10 mg/kg per day). High doses 
of probucol are known to retard atherogenesis in 
these animals [5]. One control animal died during 
the study period. After 6 months of treatment 
blood was drawn into vacutainer tubes containing 
EDTA plus 10 mg of reduced glutathione, plasma 
was prepared immediately and 0.1 mg of the anti- 
oxidant butylated hydroxytoluene added per ml. 
This treatment effectively prevents oxidation in 
vitro: in plasma of 5 normal volunteers we found 
total oxysterol levels of 1.36 pmol/l at time 0 and 
1.32 pmol/l after 6 month of storage at -80°C. 
Cholesterol oxidation products were determined 
by a modification of our previously described 
method [6]. 
The mean concentration of serum cholesterol 
was unaffected in the control animals (18.6 f 1.3 
114 
TABLE 1 
PLASMA LEVELS OF OXYSTEROLS (Fmol/l) IN 3 CON- 
TROL AND 4 PROBUCOL-TREATED WHHL RABBITS 
(MEAN (S.D.)) 
Control Probucol P 
Total oxysterols 9.15 (1.33) 4.64 (0.58) <O.Ol 
7a-Hydroxycholesterol 5.04 (0.33) 2.17 (0.64) c 0.001 
5,6c+Epoxycholestanol 0.78 (0.44) 0.39 (0.21) NS 
7&Hydroxycholesterol 0.69 (0.23) 0.54 (0.09) NS 
So-Cholestanetriol 0.88 (0.10) 0.55 (0.09) <O.Ol 
7-Ketocholesterol 1.41 (0.39) 0.84 (0.11) co.01 
25-Hydroxycholesterol 0.35 (0.13) 0.15 (0.02) < 0.05 
vs. 19.0 f 1.9 mmol/l), whereas there was a slight 
decrease in the probucol treated animals 
(17.7 f 2.4 vs. 14.2 & 1.8 mmol/I). Ingestion of a 
low dose of probucol caused a 50% difference in 
the levels of circulating cholesterol oxidation 
products (oxysterols) (Table 1). 
This study provides direct evidence that oxidis- 
ed lipoproteins occur in vivo in the circulation and 
that administration of low doses of probucol can 
prevent oxidation to a large extent, explaining its 
anti-atherogenic effect in WHHL rabbits. 
References 
Steinberg, D., Parthasarathy, S., Carew, T.E., Khoo, J.C., 
and Witztum, J.L., Beyond cholesterol: modifications of 
low-density lipoprotein that increase its atherogenicity, N. 
Engl. J. Med., 320 (1989) 915. 
Witztum, J.L. and Steinberg, D., Role of oxidized low 
density lipoprotein in atherogenesis, J. Clin. Invest., 88 
(1991) 1785. 
Salonen J.T., Yla-Herttuala, S., Yamamoto, R., Butler, 
S., Korpela, H., Salonen, R., Nyysdnen, K., Palinski, W. 
and Witztum J.L., Autoantibody against oxidised LDL 
and the progression of carotid atherosclerosis, Lancet, 
339 (1992) 883. 
Editorial, Antibodies to oxidised LDL in atherosclerosis, 
Lancet, 339 (1992) 899. 
Carew, T.E., Schwenke, D.C. and Steinberg, D., Anti- 
atherogenic effect of probucol unrelated to its 
hypocholesterolemic effect: Evidence that antioxidants in 
vivo can selectively inhibit low density lipoprotein 
degradation in macrophage-rich fatty streaks and slow the 
progression of atherosclerosis in the Watanabe heritable 
hyperlipidemic rabbit, Proc. Natl. Acad. Sci. USA, 84 
(1987) 7725. 
van de Bovenkamp P., Kosmeijer-Schuil, T.G. and Katan, 
M.B., Quantification of oxysterols in Dutch foods: Egg 
products and mixed diets, Lipids, 23 (1988) 1079. 


NARCIS 

http://dare.ubvu.vu.nl/bitstream/handle/1871/11627/xx223.pdf?sequence=1&isAllowed=y

In vivo oxidised cholesterol in atherosclerosis

Abstract

Similar works

Full text

Available Versions

VU Research Portal

DSpace at VU

NARCIS