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(Circulation. 1998;97:2012-2016.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Passive Smoking Induces Atherogenic Changes in Low-Density Lipoprotein

Miia Valkonen, MD; ; Timo Kuusi, MD, PhD

From the Department of Medicine, University of Helsinki, Finland.

Correspondence to Timo Kuusi, MD, PhD, Department of Medicine, Helsinki University Hospital, Haartmaninkatu 4, 00290 Helsinki 29, Finland.

	Abstract

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Background—According to the American Heart Association, passive smoking is an important risk factor for coronary heart disease (CHD), but the mechanisms underlying this association are not fully understood. We studied the acute effect of passive smoking on the factors that influence the development of CHD: the antioxidant defense of human serum, the extent of lipid peroxidation, and the accumulation of LDL cholesterol in cultured human macrophages, the precursors of foam cells in atherosclerotic lesions.

Methods and Results—Blood samples were collected during 2 ordinary working days from healthy, nonsmoking subjects (n=10) before and after (up to 5.5 hours) spending half an hour in a smoke-free area (day 1) or in a room for smokers (day 2). Passive smoking caused an acute decrease (1.5 hours after exposure) in serum ascorbic acid (P<.001) and in serum antioxidant defense (P<.001), a decreased capacity of LDL to resist oxidation (P<.01), and the appearance of increased amounts of lipid peroxidation end products in serum (P<.01). Finally, LDL isolated from subjects after passive smoking was taken up by cultured macrophages at an increased rate (P<.05).

Conclusions—Exposure of nonsmoking subjects to secondhand smoke breaks down the serum antioxidant defense, leading to accelerated lipid peroxidation, LDL modification, and accumulation of LDL cholesterol in human macrophages. These data provide the pathophysiological background for the recent epidemiological evidence about the increased CHD risk among passive smokers.

Key Words: lipoproteins • coronary disease • smoking • atherosclerosis

	Introduction

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Clinical and epidemiological studies have shown that involuntary exposure to environmental tobacco smoke is an important cause of heart disease and death, but only a few studies have provided pathophysiological evidence underlying this relationship.¹ It has been suggested that acute exposure to passive smoking deteriorates oxygen delivery and use in the myocardium,² causes mild coronary vasoconstriction,³ increases platelet activity in nonsmokers,⁴ and damages the endothelium, indicated by the appearance of anuclear endothelial cell carcasses in the blood.⁵ Long-term exposure to passive smoking reduces the serum level of ascorbic acid,⁶ impairs the arterial endothelial function probably through impaired endothelial nitric oxide activity,⁷ and increases the thickness of the carotid wall.⁸ Furthermore, accelerated atherosclerotic plaque development has been found in animals subjected to CS.⁹

SHS is known to contain numerous oxidants and pro-oxidants that are capable of producing free radicals and possibly initiating lipid peroxidation.¹⁰ The free radicals entering the body are first trapped by serum aqueous and lipophilic antioxidants, which interact and provide greater protection against lipid peroxidation than any antioxidant on its own. After a failure of this antioxidant barrier, LDL lipid peroxidation can take place. LDL oxidation, followed by LDL cholesterol accumulation in macrophages, is generally accepted as a key event of atherosclerosis.¹¹ Therefore, this could be one factor leading to the high incidence of CHD in smokers, who also have decreased plasma levels of certain antioxidants.¹² However, only fractional and, to some extent, controversial evidence concerning the connection between CS and lipid peroxidation has been reported so far from studies conducted with active smokers or under in vitro conditions.^{13 14 15}

To understand the pathogenesis underlining the connection between CHD and passive smoking, we assessed the acute effect of passive smoking on LDL metabolism. We started with the effect of SHS on the antioxidant barrier protecting LDL and then continued to test the effect of passive smoking on lipid peroxidation and finally on the accumulation of LDL cholesterol in cultured human macrophages.

	Methods

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Subjects
Blood samples were taken from 10 (5 female and 5 male) nonsmoking, normolipidemic subjects who ranged from 23 to 39 years of age, were taking no known medication, and were without evidence of disease. All subjects lived in smoke-free homes, worked in smoke-free environments, and were advised to avoid environmental smoke during their free time for at least 48 hours before entering the study. The samples were collected during 2 ordinary working days before (time 0) and during 6 hours of follow-up from the beginning of the exposure. The subjects spent half an hour in their normal office rooms, thus in a smoke-free area (day 1) or in a room used specifically by active smokers (day 2). Subjects had their normal breakfasts before the study and lunches during the study. They were exposed to smoke for 30 minutes in the 88-m³ ventilated room (ventilation rate, 600 s^-1), where 16 cigarettes were consumed during the exposure by active smokers. After passive smoking, the subjects continued their normal working days in smoke-free environments. All participants reported symptoms such as headache, nausea, or palpitation after passive smoking. The study was approved by the local ethics committee.

Blood samples were collected at time 0 and 1.5 and 6 hours after the beginning of the exposure into tubes kept on ice. Serum or plasma containing 1 mg/mL ethylene diamine tetra-acetate (Na₂EDTA 1 mg/mL) was separated by centrifugation at +4°C. Unless used immediately, samples were stored at -80°C and used within a 2-month period. Serum cholesterol, triglycerides, HDL cholesterol, and uric acid were measured in a Cobas Mira-S Centrifugal Analyzer (Roche Inc) with commercially available reagents of Roche (catalogue No. 0736643, 0736805, 0720674, and 0736813, respectively). Serum lipid-soluble antioxidants (available from seven subjects), aqueous antioxidants, and the combined capacity of all serum antioxidants to resist artificially induced peroxidation, ie, the TRAP, were determined as described recently.¹⁶

LDL was isolated by rate-zone ultracentrifugation in a density gradient. Before oxidation, EDTA was separated from LDL by use of small dextran-sulfate affinity columns (Liposorber LA-15, Kaneka Co). Lipid peroxidation was initiated by adding freshly prepared CuSO₄ solution to a final concentration of 10.4 µmol/L, and the formation of conjugated dienes was monitored at a wavelength of 234 nm with standard techniques using a computerized system.¹⁶ The resistance of LDL to oxidation was derived from the length of the lag time (minutes) before the propagation of the reaction. The TBARS in serum and LDL were determined as described previously.¹⁷

Human monocytes (>95% pure) were obtained from healthy volunteers and isolated in a discontinuous gradient at 1.065 g/mL by centrifugation for 20 minutes at 2000g.¹⁸ Before this, the white cell pellet was preconditioned according to Recalde¹⁹ at 320 mOsm/L. On average, 45 µg of cellular protein was added per culture well, and the cells were cultured for 5 days, after which the monocyte layers were washed and the culture medium changed to contain 300 µg/mL of LDL. Lipid accumulation in the monocyte macrophages was determined by measuring the incorporation of (1-¹⁴C)-oleate (52 mCi/mmol) into the cellular cholesteryl oleate (ACAT assay) as described by Basu et al.²⁰ LDL isolated after passive smoking and after the control period from each subject were studied in the same cell culture plate simultaneously. The amount of cellular protein was not influenced significantly by any type of LDL used in this study.

Statistical analysis was done by use of the Systat statistical package. Significances are given as an overall difference between the values obtained after the subjects spent half an hour in a smoke-free area or in a smoking room and were tested by ANOVA for repeated measurements. The values are given as mean±SE.

	Results

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Passive smoking resulted in a major loss of serum antioxidant defense in all the nonsmoking subjects. A one-third decrease in serum ascorbic acid took place (P<.001), starting 1.5 hours from the beginning of the exposure to smoke and lasting until the end of the follow-up, ie, a total of 6 hours (Table 1). Furthermore, protein sulfhydryl groups (SH groups) decreased gradually for 6 hours by 26% (P<.063) (Table 1). The smoke exposure did not affect serum lipid-soluble antioxidants (vitamin E, retinol, and ß-carotene) and uric acid (Table 1). No significant changes took place in any of these parameters after the control period in a smoke-free area.

View this table: [in this window] [in a new window]   Table 1. Serum Antioxidants and TRAP (Mean±SE) in Healthy Subjects (n=10) Before and After Passive Smoking

The total serum antioxidant defense can be quantified by determining the TRAP, which can be done either experimentally from the serum samples or by calculating the sum capacity of all major antioxidants to trap free radicals (Table 1). Passive smoking caused a significant (31%, P<.01; Fig 1) and a minor (10%, nonsignificant) decrease 1.5 hours after the beginning of the exposure in experimental and calculated TRAP values, respectively. Notably, the mean values of both experimental and calculated TRAP returned to close to baseline at the end of the follow-up in all subjects. At baseline, the calculated TRAP values in these subjects ranged from 474 to 929 µmol/L, which were 50% lower than the measured TRAP values (931 to 1680 µmol/L) (Table 1). The baseline TRAP values did not differ significantly between the 2 days of the study (Table 1), and no significant change was found after the control period in a smoke-free area (day 1) (Fig 1).

View larger version (30K): [in this window] [in a new window]   Figure 1. Effect of passive smoking on serum antioxidant defense (measured TRAP) and on serum lipid peroxidation end products (TBARS). Individual changes were noted after the subjects spent half an hour in a smoke-free area or in a smoking room. Exposure period was 30 minutes (). ]

Passive smoking did not affect serum lipid concentrations, but simultaneous with the deterioration of the antioxidant defense, a significant (19%, P<.01) decrease in the resistance of LDL to Cu²⁺-initiated oxidation was found (Table 2 and Fig 2). This was first observed 1.5 hours after the beginning of passive smoking, and the lag times remained still 11% shorter than at baseline at the end of the follow-up. Furthermore, the initial amount of conjugated dienes in freshly isolated LDL, without further modifications, was significantly higher after passive smoking than before the exposure to smoke or after the control period (P<.001). Also, the end products of lipid peroxidation in serum increased after passive smoking, indicated by a significant increase in the small aldehyde substances, TBARS, that are released from polyunsaturated fatty acids during their oxidation (P<.01, Fig 1 and Table 2). The TBARS were not detectable in LDL with no further modification but were 1.5 times higher in Cu²⁺-oxidized LDL 1.5 to 6 hours after the beginning of passive smoking than after exposure to normal air (P<.05). No significant changes took place in these parameters after the control period in a smoke-free area.

View this table: [in this window] [in a new window]   Table 2. Indexes of Lipid Peroxidation and Cholesterol Esterification Rate (ACAT Activity) in Cultured Human Macrophages Before and After Passive Smoking

View larger version (28K): [in this window] [in a new window]   Figure 2. Effect of passive smoking on the capacity of LDL to resist peroxidation (lag time) and on the accumulation of LDL cholesterol in cultured human macrophages (ACAT activity). Individual changes were noted after subjects spent half an hour in a smoke-free area or in a smoking room. Exposure period was 30 minutes ().

In the final step of the lipid oxidation hypothesis, the end products of lipid peroxidation modify apolipoprotein B in LDL. This leads to a more rapid and unregulated uptake of LDL cholesterol by macrophages and to foam cell formation. To study the influence of passive smoking on LDL cholesterol uptake by macrophages, we isolated LDL from the subjects before and after they spent half an hour in a smoke-free area (day 1) or in a smokers' room (day 2). The macrophages were incubated with 300 µg/mL of freshly isolated LDL without further modification. Incubation of cells with LDL separated 1.5 to 6 hours from the beginning of passive smoking induced a 1.6- to 2.3-times-higher synthesis of cholesteryl oleate in macrophages than LDL separated before the exposure (P<.05; Fig 2). No significant difference in the cellular cholesteryl oleate synthesis was observed at baseline between the 2 days of the study or after the control period in a smoke-free area (Table 2).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Acute exposure of a nonsmoking subject to passive smoking resulted in deterioration of serum antioxidant defense, accelerated lipid peroxidation, and accumulation of LDL cholesterol in cultured human macrophages. These events were observed even after a very short period (30 minutes) of passive smoking. Indeed, it has previously been suggested that the cardiovascular system is extremely sensitive to the chemicals in environmental tobacco smoke.¹ Furthermore, the oxidative stress induced by SHS may have a more prominent effect on a nonsmoking subject than on an active smoker whose cardiovascular system has adapted to CS.¹

Oxidative stress induced by acute passive smoking significantly decreased plasma ascorbic acid and caused a minor, nonsignificant decrease in protein sulfhydryl groups, reflecting increased use of these antioxidants. This is in line with previous studies demonstrating that long-term exposure to SHS decreases plasma ascorbic acid in both active and passive smokers.^{7 12} Furthermore, in vitro data exposing human plasma to CS suggest that ascorbic acid is the first antioxidant to be consumed.¹⁴ However, adequate quantification of serum antioxidant defense can be obtained only by measurement of the combined capacity of all antioxidants to resist peroxidation, the TRAP.¹⁶ A one-third reduction in the experimental TRAP values was evident after passive smoking, but the values returned to close to normal at the end of the follow-up. These changes were much larger than could be calculated from changes in the serum levels of individual antioxidants. These findings indicate changes in the cooperation between antioxidants, best known between vitamin E and ascorbate, and contribution of some unknown antioxidants.¹⁶ Part of this discrepancy can also be explained by serum bilirubin, carotenoids, retinols, and serum antioxidant enzymes, which are not included in the calculations, because their contribution to TRAP and their action as chain-breaking antioxidants have been suggested to be negligible.¹⁶ Thus, in accordance with previous reports, throughout this study, all the TRAP values measured directly from the serum samples were up to 50% higher than those calculated as the sum of the capacity of major antioxidants to trap free radicals (Table 1).

Simultaneous with the failure in the antioxidant defense, a reduction in the resistance of isolated LDL to Cu²⁺-stimulated oxidation after passive smoking could be demonstrated. Previously, the reduction in the resistance of isolated LDL to oxidation has been shown to correlate with the severity of coronary atherosclerosis.²¹ Because LDL is separated from its aqueous surroundings, the lag period reflects the lipophilic antioxidants in LDL, such as -tocopherol. In vivo LDL will also interact with serum water-soluble antioxidants such as ascorbic acid, which protects LDL from lipid peroxidation by regenerating vitamin E from tocopheryl radicals.²² Thus, the decrease in serum ascorbic acid after passive smoking may increase the amount of tocopheryl radicals, which can act as reducing agents and possibly accelerate metal-ion–dependent oxidative damage.²³ Furthermore, the low levels of ascorbic acid in subendothelial spaces could make LDL more susceptible to oxidative modification at this site in vivo.²⁴ We have previously shown that the combined antioxidant capacity and the resistance of LDL to oxidation can be increased by dietary supplementation in healthy subjects with vitamin E.¹⁶ The present results indicate that impairment of vitamin E regeneration by the loss of ascorbic acid during SHS-induced oxidative stress seems to decrease them both.

The amount of conjugated dienes in freshly isolated LDL was 10% higher after passive smoking than before the smoke exposure and 20% higher than after the control period (P<.001, data not shown), but no lipid peroxidation end products (TBARS) were detectable in LDL. TBARS may have been removed as water-soluble aldehydes from LDL during isolation, because they were significantly higher in serum after passive smoking than after spending the same time in normal air. When the oxidation process of LDL is continued by adding Cu²⁺, TBARS are produced at an accelerated rate in CS-modified LDL compared with control LDL. This indicates that the peroxidation process has already been started during SHS exposure. Thus, CS-modified LDL may resemble the minimally modified LDL and be more susceptible to further peroxidation by Cu²⁺. The minimally modified LDL has been shown to induce platelet aggregation, to cause retraction of vascular smooth muscle cells, to be cytotoxic to endothelial cells, and to cause induction of macrophage chemotactic cytokines.²⁵ Notably, many of the above effects are caused by passive smoking.^{3 4 5 8}

Definitive evidence about the atherogenic nature of CS-modified LDL is its interaction with cultured human macrophages, which store cholesterol and develop to foam cells. The cholesteryl esterification reaction reflects the amount of cholesterol stored in these cells.²⁰ Incubation of cells with LDL, separated 1.5 to 6 hours after passive smoking without further modifications, induced 1.6- to 2.3-times-higher synthesis of cholesteryl oleate in macrophages than LDL separated before the exposure, respectively. The CS-modified LDL may also stimulate the macrophages to release free radicals, further modifying these lipoproteins.¹³ Whatever the mechanism, the results demonstrate that even after a short period of passive smoking, increasing amounts of LDL cholesterol are taken up by human macrophages. In accordance, 2 to 4 hours of exposure of rats to environmental tobacco smoke has recently been shown to increase LDL accumulation in perfused arteries.²⁶

An increasing number of reports has documented the harmful effects of environmental tobacco smoke.^{27 28 29} We found that a short period of passive smoking changed LDL metabolism, favoring the progression of atherosclerosis. The present results demonstrate one mechanism by which SHS could increase the risk of CHD, already shown in epidemiological and clinical studies.

	Selected Abbreviations and Acronyms

 

CHD = coronary heart disease CS = cigarette smoke SHS = secondhand smoke TBARS = thiobarbituric acid reactive substances TRAP = total peroxyl radical trapping potential of serum

	Acknowledgments

 
This study was supported by Finnish Heart Research Foundation and Aarne Koskelo Foundation.

Received September 23, 1997; revision received December 18, 1997; accepted January 14, 1998.

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