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Increase of isoprostane 8-epi-PGF2 αafter restarting smoking
Prostaglandins, Leukotrienes and Essential FattyAcids (2001) 64(6), 307^310 & 2001 Harcourt Publishers Ltd doi:10.1054/plef.2001.0277, available online at http://www.idealibrary.com on
Increase of isoprostane 8-epi-PGF2a after restarting smoking F. Chehne,1 A. Oguogho,1 G. Lupattelli,2 A. C. Budinsky,3 B. Palumbo,4 H. Sinzinger1,5 1
Department of Nuclear Medicine, University of Vienna, Austria Department of Internal Medicine, University of Perugia, Italy 3 Clinical Division of Oncology, Department of Internal Medicine I, University of Vienna, Austria 4 1nstitute of Nuclear Medicine, University of Perugia, Italy 5 Wilhelm Auerswald Atherosclerosis Research Group (ASF) Vienna, Austria 2
Summary Isoprostanes are known as reliable markers of in vivo oxidation injury. Cigarette smoking has been shown to be associated with a significant increase in 8-epi-PGF2a, a major member of this family of compounds. Quitting smoking reduces 8-epi-PGF2a values to normal within a couple of weeks only. In this follow-up we checked the 8-epi-PGF2a, values in plasma, serum and urine in 28 people who restarted smoking after a quitting attempt of various duration. 8-epi-PGF2a shows a certain increase after restarting smoking reaching a maximum after already1week.Continuation of smoking does not significantly further increase 8-epi-PGF2a These data indicate a fast response of restarting as on quitting smoking on in vivo oxidation injury. The oxidation injury reflected by 8-epi-PGF2a may be a key pathogenetic mechanism in smoking-induced vascular injury. & 2001 Harcourt Publishers Ltd
INTRODUCTION Cigarette smoking is the most relevant risk factor for the development of atherosclerosis.1 Although the enhanced cardiovascular risk in cigarette smokers is well established,2,3 the causative biochemical mechanisms behind are far away from being understood yet. Cigarette smoking is associated with an oxidation injury resulting in the modification of lipoproteins and in particular of LDL.4 The molecule thus is no longer recognized by the classical regulated LDL-receptor5 and consequently taken up via the scavenger receptor of macrophages in an unregulated manner.6 This results in excessive accumulation of modified LDL in monocytes/macrophages thereby becoming foam cells. This mechanism
is recognized as the hallmark of the human atherosclerotic lesion. Oxidation of LDL in vitro has been demonstrated to be paralleled by formation of IP and in particular of 8-epi-PGF2a.7 In chronic cigarette smokers increased 8-epi-PGF2a has been demonstrated in the arterial wall immunochemically as well as immunohistochemically8–11 and also in plasma, serum and urine.12 Quitting smoking results in decreased vascular risk.13 Reduction of risk factors and respective consultation is a key interventional strategy in patients with clinically manifested atherosclerosis and/or lipid metabolic disorders. We therefore examined plasma, serum and urinary 8-epi-PGF2a in people restarting smoking after an unsuccessful quitting attempt for at least 4 weeks.
Received 1December 2000 Accepted 17 January 2001
MATERIALS AND METHODS
Correspondence to: Prof Dr Helmut Sinzinger,Wilhelm Auerswald Atherosclerosis Research Group (ASF) Vienna, Nadlergasse 1, A-1090 Vienna, Austria.Tel.: +43 14082633; Fax: +43 14081366; E-mail: [email protected] Dr Anthony Oguogho was on sabbatical leave from the Department of Physiology, Faculty of Basic Medical Sciences, Edo State University, Ekpoma, Nigeria, supported by the Austrian Academic Exchange Division (ÚAAD).
Twenty eight (16 males, 12 females) restarting cigarette smoking after an unsuccessful quitting period of at least 4 weeks were monitored for 4 weeks during continuous cigarette smoking. They were grouped into patients with and without clinically manifested atherosclerosis as well as according to other risk factors being present, such as
& 2001Harcourt Publishers Ltd
Prostaglandins, Leukotrienes and Essential FattyAcids (2001) 64(6), 307^310
308
Chehne et al.
hypertension and elevated blood lipids (for characteristics see Table 1). Blood was drawn in the morning after an at least 12 h overnight fasting for creatinine and 8-epi-PGF2a-determination. A 24 h urine was collected at the same time and an aliquot stored at 7708C after assessing total volume for determination. Values during cigarette smoking before quitting, 44 weeks after quitting as well as 1, 3, 5, 7, 14, 21 and 28 days after restarting were investigated. The patients were not changing any dietary habit or medication during the last 4 weeks preceding the quitting attempt. No pharmacological add to support quitting was used.
Serum 8-epi-PGF2a Blood was drawn into glass vials. Vials were placed immediately into a water bath at 378C for exactly 60 min. Serum was removed after centrifugation (48C, l0006g, 10 min) and stored until determination (no longer than 2 weeks at 57708C) as described.11 The interassay variability amounted 3.8+1.2%, the intraassay variability was 1.9+0.7%. Normal value: 150–120 pg/ml (n = 17).
Plasma 8-epi-PGF2a Blood samples were anticoagulated with 2% EDTA and 1 mg/ml (final blood volume) acetylsalicylic acid (ASA). Immediate centrifugation at 48C to obtain plasma was done at 10006g for 10 min. Plasma was removed and stored at 57708C for not longer than 2 weeks until determination. The interassay variability was 5.5+1.7%, the intraassay variability 2.5+0.7%. Normal value: 520 pg/ml (n = 11).
Urinary 8-epi-PGF2a Urine was collected over a period of 24 h. 10 ml aliquots were adjusted to pH 4.0 with formic acid and taken for extraction. The eluate was subjected to silicic acid chromatography and further eluted. This final eluate was dried, recovered in buffer and assayed after dilution.
Cross reactivity of the antibody with PGs was 52%. Values are given in pg 8-epi-PGF2a/mg creatinine. The interassay variability was 6.4+2.3%, the intraassay variability 2.7+0.8%. Normal values: 150–250 pg/mg creatinine (n = 14).
Statistical analysis Values are presented as x +SD; calculation for significance was done using ANOVA analysis of variance. A P-value of 50.01 was considered as significant. RESULTS In patients with HC the IP-values in plasma (Fig. l), serum (Fig. 2) and urine (Fig. 3) are higher as compared to NC. Values of 8-epi-PGF2a in plasma, serum as well as urine in smokers are significantly (P50.01) above the ones during quitting. After restarting cigarette smoking, 8-epi-PGF2a shows an immediate increase, reaching significance after 5 (plasma), 3 (serum) and 7 (urine) days and a maximum after already about 1 week. These values are corresponding to the ones before the quitting attempt. Thereafter, no further significant change in 8-epi-PGF2a can be seen. Depending on the type and number of risk factors there is a trend towards higher 8-epi-PGF2a, however, the kinetics observed during restarting are identical in all the subgroups. Hypertension (Figs 4–6) apparently has no relevant influence on 8-epi-PGF2a. DISCUSSION IP are a recently discovered new family of prostaglandin isomers formed by free radical catalyzed action from arachidonic acid14,15 in vivo in men. They may play an essential role in human atherogenesis. 8-epi-PGF2a is among the most important and the best investigated substances of the F2-IP. The effect of quitting and restarting cigarette smoking on IP is not only easy to standardize, but has also an important value as to the risk assessment in these patients16 as well as the kinetics of oxidation injury. It has been shown17 that IP are rather stable showing no
Table 1 Patients’characteristics Mainfested atherosclerosis
Sex (m/f)
Age (a)
Duration of smoking (a)
NO þ HT þ HC HTþHC
2/2 3/2 4/2 4/2
53^67 37^58 32^66 37^61
5^37 7^41 5^42 11^37
Non-manifested atherosclerosis þ HC
Sex (m/f) 3/4
Age (a) 30^65
Duration of smoking (a) 11^44
HC . . . hypercholesterolemia, HT. . . hypertension; NO . . . no other risk factors Prostaglandins, Leukotrienes and Essential FattyAcids (2001) 64(6), 307^310
& 2001Harcourt Publishers Ltd
Increase of isoprostane 8-epi-PGF2a after restarting smoking
Fig. 1 Plasma 8-epi-PGF2a after restarting smoking.Values are given in x+SD; ^HC þ (n = 6); &NC ^ (n = 7). Restarting smoking causes a sudden increase in 8-epi-PGF2a being more pronounced in HC vs NC.
Fig. 2 Serum 8-epi-PGF2a, after restarting smoking.Values are given in x+SD; abbreviations and patients as in Figure1.The kinetics of 8-epi-PGF2a during quitting and restarting smoking are identical, the values being significantly higher in HC vs NC at all the intervals examined.
Fig. 3 Urinary 8-epi-PGF2a after restarting smoking.Data in x+SD; for abbreviations see Figure1. Urinary 8-epi-PGF2a shows identical kinetics after restarting smoking.The difference between HC and NC is the smallest among the compartments examined.
diurnal variations. The small variations we saw after 1 week after restarting smoking are supporting these data. Cigarette smokers apparently show highly elevated IP in blood and urine as well.18 Similar findings originally have & 2001Harcourt Publishers Ltd
309
Fig. 4 Plasma 8-epi-PGF2a after restarting smoking. Hyper- vs Normocholesterolemia & Ath = clinically manifested atherosclerosis; ^Ath þ HT = atherosclerosis þ hypertension; ~ Ath þ HC þ HT = atherosclerosis þ hypercholesterolemia þ hypertension.The increase of 8-epi-PGF2a after restarting smoking somewhat differs between groups, plasma levels reaching their maximum between1and 2 weeks.
Fig. 5 Serum 8-epi-PGF2a after restarting smoking. Hyper- vs Normocholesterolemia. Abbreviations as in Figure 4. Serum kinetics are similar after restarting cigarette smoking, HC apparently resulting at significantly higher 8-epi-PGF2a values at each time point examined.
Fig. 6 Urine 8-epi-PGF2a after restarting smoking. Hyper- vs Normocholesterolemia. For abbreviations see Figure 4.The urinary 8-epi-PGF2a in patients with HC tends to increase faster reaching a maximum after already 5 days as compared to the other two groups (14 and 2 1days, respectively).
been reported by Morrow’s group.19 The increase after restarting smoking is most pronounced with urinary and plasma values. This is similar to the behaviour at quitting. While hypercholesterolemia is associated with increased
Prostaglandins, Leukotrienes and Essential FattyAcids (2001) 64(6), 307^310
310
Chehne et al.
8-epi-PGF2a12 also in this setting, hypertension does not significantly affect the respective values. 15-hydroxyperoxy-arachidonic acid formed during in vivo oxidation injury is a potent inhibitor of PGI2synthesis.20 Furthermore, the other most important endothelial mediator, nitric oxide, is readily transformed by free radicals into peroxynitrite. Vascular 8-epiPGF2a,8,9,12 apparently due to the on-site modification of LDL is a reliable indicator of atherogenicity which has been studied in human and experimental animal vascular tissue. This ratio (8-epi-PGF2a/PGI2) showed a good correlation8,12 to the risk factors and in particular to cigarette smoking and hyperlipidemia. 8-epi-PGF2a is a potent vasoconstrictor which has been demonstrated in coronary arteries21 and human lymphatics.22 It is a mitogen23 and a stimulator of atherogenic mediators.24 It induces shape-change but has a very mild proaggregatory action25 only. 8-epi-PGF2a is also released from human platelets not depending on the antioxidant status and the respective action of a cyclooxygenase blockade. Whether this release per se is affected by cigarette smoking has not been studied so far. Our results indicate that after only a few days after restarting of smoking IP as an indicator of in vivo oxidation injury are significantly enhanced, while after quitting smoking they are rapidly decreasing. This implies that more LDL is modified when people are smoking reflecting a significant in vivo atherogenic potential of LDL. The value of IP-follow-up to monitor smoking behaviour as well as to assess in vivo oxidation injury on a routine base still needs to be elucidated.
ACKNOWLEDGEMENT The valuable help of Eva Unger in preparing and typing the manuscript is gratefully acknowledged.
REFERENCES 1. Krupski W. C. The peripheral vascular consequence of smoking. Ann Vasc Surg 1991; 5: 91–95. 2. Ahmed S. S., Moschos C. B., Lyons M. M., Oldewurtel H. A., Coumbis R. J., Regan T. J. Cardiovascular effects of long-term cigarette smoking and nicotine administration. Am J Cardiol 1976; 37: 33–40. 3. Miettinen O. S., Neff R. K., Jick H. Cigarette smoking and nonfatal myocardial infarction: rate ratio in relation to age, sex and predisposing conditions. Am J Epidemiol 1976; 103: 30–36. 4. Scheffler E., Wirest E., Woehrle J., Otto I., Schulz I., Huber L. Smoking influences the atherogenic potential of low-density lipoprotein. Clin Invest 1992; 70: 263–265. 5. Steinberg D., Parthasarathy S., Carew T. E., Khoo J. C., Witztum J. L. Beyond cholesterol; modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989; 320: 915–924. 6. Steinberg D. Low-density lipoprotein oxidation and its pathobiological significance. J Biol Chem 1997; 272: 2063–2066.
7. Gopaul N. K., Nourooz-Zadeh J., Molex A. I., Anggard E. E. Formation of PGF2-isoprostanes during oxidative modification of low-density lipoprotein. Biochem Biophys Res Commun 1994; 200: 338–343. 8. Oguogho A., Kritz H., Wagner O., Sinzinger H. 6-oxo-PGF1a and 8-epi-PGF2a in the arterial wall layers of various species — a comparison between intact and atherosclerotic arteries. Prostagl Leukotr Essent Fatty Acids 2000 (accepted). 9. Pratico D., Luliano L., Spagnoli L., et al. Monocytes in human atherosclerotic plaque contain high levels of 8-epiPGF2a: an index of oxidative stress in vivo. Circulation 1996; 94: 277A. 10. Sinzinger H., Oguogho A., Kritz H., Pirich C., Wagner O., Mehrabi M., Peskar B. A. Isoprostanes in atherosclerotic lesions. Atherosclerosis 1997; 134: 276A. 11. Oguogho A., Karanikas G., Kritz H., Riess G., Wagner O., Sinzinger H. 6-oxo-PGF1a and 8-epi-PGF2a in human atherosclerotic vascular tissue. Prostagl Leukotr Essent Fatty Acids 1999; 60: 129–134. 12. Oguogho A., Mehrabi M., Sinzinger H. Increased plasma, serum and urinary 8-epi-prostaglandin F2a in heterozygous hypercholesterolemia. Wr klin Wschr 1999; 111: 113–118. 13. Warner K. E., Must H. A. Premature deaths avoided by the antismoking campaign. Am J Publ Health 1983; 73: 672–677. 14. Arakil Aghajanian A., Oguogho A., Sinzinger H. Isoprostane, eine neue Substanzgruppe in der Angiologie — in der Zukunft von Bedeutung? VASA 1997; 26: 65–69. 15. Morrow J. D., Roberts II L. J. The isoprostanes: current knowledge and direction of future research. Biochem Pharmacol 1996; 51: l–9. 16. Pilz H., Oguogho A., Chehne F., Lupattelli G., Palumbo B., Sinzinger H. Quitting cigarette smoking results in a fast improvement of in vivo oxidation injury (determined via plasma serum and urinary isoprostane). Thromb Res 2000; 99: 209–221. 17. Helmersson J., Basu S. F2-isoprostane excretion rate and diurnal variation in human urine. Prostagl Leukotr Essent Fatty Acids 1999; 61: 203–205. 18. Reilly M. P., Delanty N., Lawson J. A., FitzGerald G. A. Modulation of oxidant stress in-vivo in chronic cigarette smokers. Circulation 1996; 94: 19–25. 19. Morrow J. D., Frei B., Longmore A. W., Graziano J. M., Lynch S. M., Shyr Y., Strauss W. E., Oates J. A., Roberts II L. J. Increase in circulating products of lipid peroxidation (F2-isoprostanes in smokers. Smoking as a cause of oxidative damage. New Engl J Med 1995; 332: 1198–1203. 20. Szczeklik A., Gryglewski R. J. Low-density lipoproteins (LDL) are carriers for lipid peroxides and inhibit prostacyclin (PGI2) biosynthesis in arteries. Artery 1980; 7: 477–495. 21. Kromer B. M., Tippins J. R. Coronary artery constrictions by the isoprostane 8-epi-prostaglandins F2a. Brit J Pharm 1996; 119: 1276–1280. 22. Sinzinger H., Oguogho A., Kaliman J. Isoprostane 8-epiprostaglandin-F2a is a potent contractor of human peripheral lymphatics. Lymphology 1997; 30: 155–169. 23. Fukunaga M., Takahashi K., Badr K. F. Vascular smooth muscle action and receptor interactions of 8-isoPGE2, and E2-isoprostane. Biochem Biophys Res Commun 1993; 195: 507–515. 24. Fukunaga M., Yura T., Badr K. F. Stimulatory effect of 8-epi-PGF2a and F2-isoprostane, on endothelin-1 release. J Cardiovasc Pharm 1995; 26: 5l–52. 25. Leitinger N., Blazek I., Sinzinger H. The influence of isoprostanes on ADP-induced platelet aggregation and cyclic AMP-generation in human platelets. Thromb Res 1997; 86: 337–342.
Prostaglandins, Leukotrienes and Essential FattyAcids (2001) 64(6), 307^310
& 2001Harcourt Publishers Ltd
Increase of isoprostane 8-epi-PGF2a after restarting smoking F. Chehne,1 A. Oguogho,1 G. Lupattelli,2 A. C. Budinsky,3 B. Palumbo,4 H. Sinzinger1,5 1
Department of Nuclear Medicine, University of Vienna, Austria Department of Internal Medicine, University of Perugia, Italy 3 Clinical Division of Oncology, Department of Internal Medicine I, University of Vienna, Austria 4 1nstitute of Nuclear Medicine, University of Perugia, Italy 5 Wilhelm Auerswald Atherosclerosis Research Group (ASF) Vienna, Austria 2
Summary Isoprostanes are known as reliable markers of in vivo oxidation injury. Cigarette smoking has been shown to be associated with a significant increase in 8-epi-PGF2a, a major member of this family of compounds. Quitting smoking reduces 8-epi-PGF2a values to normal within a couple of weeks only. In this follow-up we checked the 8-epi-PGF2a, values in plasma, serum and urine in 28 people who restarted smoking after a quitting attempt of various duration. 8-epi-PGF2a shows a certain increase after restarting smoking reaching a maximum after already1week.Continuation of smoking does not significantly further increase 8-epi-PGF2a These data indicate a fast response of restarting as on quitting smoking on in vivo oxidation injury. The oxidation injury reflected by 8-epi-PGF2a may be a key pathogenetic mechanism in smoking-induced vascular injury. & 2001 Harcourt Publishers Ltd
INTRODUCTION Cigarette smoking is the most relevant risk factor for the development of atherosclerosis.1 Although the enhanced cardiovascular risk in cigarette smokers is well established,2,3 the causative biochemical mechanisms behind are far away from being understood yet. Cigarette smoking is associated with an oxidation injury resulting in the modification of lipoproteins and in particular of LDL.4 The molecule thus is no longer recognized by the classical regulated LDL-receptor5 and consequently taken up via the scavenger receptor of macrophages in an unregulated manner.6 This results in excessive accumulation of modified LDL in monocytes/macrophages thereby becoming foam cells. This mechanism
is recognized as the hallmark of the human atherosclerotic lesion. Oxidation of LDL in vitro has been demonstrated to be paralleled by formation of IP and in particular of 8-epi-PGF2a.7 In chronic cigarette smokers increased 8-epi-PGF2a has been demonstrated in the arterial wall immunochemically as well as immunohistochemically8–11 and also in plasma, serum and urine.12 Quitting smoking results in decreased vascular risk.13 Reduction of risk factors and respective consultation is a key interventional strategy in patients with clinically manifested atherosclerosis and/or lipid metabolic disorders. We therefore examined plasma, serum and urinary 8-epi-PGF2a in people restarting smoking after an unsuccessful quitting attempt for at least 4 weeks.
Received 1December 2000 Accepted 17 January 2001
MATERIALS AND METHODS
Correspondence to: Prof Dr Helmut Sinzinger,Wilhelm Auerswald Atherosclerosis Research Group (ASF) Vienna, Nadlergasse 1, A-1090 Vienna, Austria.Tel.: +43 14082633; Fax: +43 14081366; E-mail: [email protected] Dr Anthony Oguogho was on sabbatical leave from the Department of Physiology, Faculty of Basic Medical Sciences, Edo State University, Ekpoma, Nigeria, supported by the Austrian Academic Exchange Division (ÚAAD).
Twenty eight (16 males, 12 females) restarting cigarette smoking after an unsuccessful quitting period of at least 4 weeks were monitored for 4 weeks during continuous cigarette smoking. They were grouped into patients with and without clinically manifested atherosclerosis as well as according to other risk factors being present, such as
& 2001Harcourt Publishers Ltd
Prostaglandins, Leukotrienes and Essential FattyAcids (2001) 64(6), 307^310
308
Chehne et al.
hypertension and elevated blood lipids (for characteristics see Table 1). Blood was drawn in the morning after an at least 12 h overnight fasting for creatinine and 8-epi-PGF2a-determination. A 24 h urine was collected at the same time and an aliquot stored at 7708C after assessing total volume for determination. Values during cigarette smoking before quitting, 44 weeks after quitting as well as 1, 3, 5, 7, 14, 21 and 28 days after restarting were investigated. The patients were not changing any dietary habit or medication during the last 4 weeks preceding the quitting attempt. No pharmacological add to support quitting was used.
Serum 8-epi-PGF2a Blood was drawn into glass vials. Vials were placed immediately into a water bath at 378C for exactly 60 min. Serum was removed after centrifugation (48C, l0006g, 10 min) and stored until determination (no longer than 2 weeks at 57708C) as described.11 The interassay variability amounted 3.8+1.2%, the intraassay variability was 1.9+0.7%. Normal value: 150–120 pg/ml (n = 17).
Plasma 8-epi-PGF2a Blood samples were anticoagulated with 2% EDTA and 1 mg/ml (final blood volume) acetylsalicylic acid (ASA). Immediate centrifugation at 48C to obtain plasma was done at 10006g for 10 min. Plasma was removed and stored at 57708C for not longer than 2 weeks until determination. The interassay variability was 5.5+1.7%, the intraassay variability 2.5+0.7%. Normal value: 520 pg/ml (n = 11).
Urinary 8-epi-PGF2a Urine was collected over a period of 24 h. 10 ml aliquots were adjusted to pH 4.0 with formic acid and taken for extraction. The eluate was subjected to silicic acid chromatography and further eluted. This final eluate was dried, recovered in buffer and assayed after dilution.
Cross reactivity of the antibody with PGs was 52%. Values are given in pg 8-epi-PGF2a/mg creatinine. The interassay variability was 6.4+2.3%, the intraassay variability 2.7+0.8%. Normal values: 150–250 pg/mg creatinine (n = 14).
Statistical analysis Values are presented as x +SD; calculation for significance was done using ANOVA analysis of variance. A P-value of 50.01 was considered as significant. RESULTS In patients with HC the IP-values in plasma (Fig. l), serum (Fig. 2) and urine (Fig. 3) are higher as compared to NC. Values of 8-epi-PGF2a in plasma, serum as well as urine in smokers are significantly (P50.01) above the ones during quitting. After restarting cigarette smoking, 8-epi-PGF2a shows an immediate increase, reaching significance after 5 (plasma), 3 (serum) and 7 (urine) days and a maximum after already about 1 week. These values are corresponding to the ones before the quitting attempt. Thereafter, no further significant change in 8-epi-PGF2a can be seen. Depending on the type and number of risk factors there is a trend towards higher 8-epi-PGF2a, however, the kinetics observed during restarting are identical in all the subgroups. Hypertension (Figs 4–6) apparently has no relevant influence on 8-epi-PGF2a. DISCUSSION IP are a recently discovered new family of prostaglandin isomers formed by free radical catalyzed action from arachidonic acid14,15 in vivo in men. They may play an essential role in human atherogenesis. 8-epi-PGF2a is among the most important and the best investigated substances of the F2-IP. The effect of quitting and restarting cigarette smoking on IP is not only easy to standardize, but has also an important value as to the risk assessment in these patients16 as well as the kinetics of oxidation injury. It has been shown17 that IP are rather stable showing no
Table 1 Patients’characteristics Mainfested atherosclerosis
Sex (m/f)
Age (a)
Duration of smoking (a)
NO þ HT þ HC HTþHC
2/2 3/2 4/2 4/2
53^67 37^58 32^66 37^61
5^37 7^41 5^42 11^37
Non-manifested atherosclerosis þ HC
Sex (m/f) 3/4
Age (a) 30^65
Duration of smoking (a) 11^44
HC . . . hypercholesterolemia, HT. . . hypertension; NO . . . no other risk factors Prostaglandins, Leukotrienes and Essential FattyAcids (2001) 64(6), 307^310
& 2001Harcourt Publishers Ltd
Increase of isoprostane 8-epi-PGF2a after restarting smoking
Fig. 1 Plasma 8-epi-PGF2a after restarting smoking.Values are given in x+SD; ^HC þ (n = 6); &NC ^ (n = 7). Restarting smoking causes a sudden increase in 8-epi-PGF2a being more pronounced in HC vs NC.
Fig. 2 Serum 8-epi-PGF2a, after restarting smoking.Values are given in x+SD; abbreviations and patients as in Figure1.The kinetics of 8-epi-PGF2a during quitting and restarting smoking are identical, the values being significantly higher in HC vs NC at all the intervals examined.
Fig. 3 Urinary 8-epi-PGF2a after restarting smoking.Data in x+SD; for abbreviations see Figure1. Urinary 8-epi-PGF2a shows identical kinetics after restarting smoking.The difference between HC and NC is the smallest among the compartments examined.
diurnal variations. The small variations we saw after 1 week after restarting smoking are supporting these data. Cigarette smokers apparently show highly elevated IP in blood and urine as well.18 Similar findings originally have & 2001Harcourt Publishers Ltd
309
Fig. 4 Plasma 8-epi-PGF2a after restarting smoking. Hyper- vs Normocholesterolemia & Ath = clinically manifested atherosclerosis; ^Ath þ HT = atherosclerosis þ hypertension; ~ Ath þ HC þ HT = atherosclerosis þ hypercholesterolemia þ hypertension.The increase of 8-epi-PGF2a after restarting smoking somewhat differs between groups, plasma levels reaching their maximum between1and 2 weeks.
Fig. 5 Serum 8-epi-PGF2a after restarting smoking. Hyper- vs Normocholesterolemia. Abbreviations as in Figure 4. Serum kinetics are similar after restarting cigarette smoking, HC apparently resulting at significantly higher 8-epi-PGF2a values at each time point examined.
Fig. 6 Urine 8-epi-PGF2a after restarting smoking. Hyper- vs Normocholesterolemia. For abbreviations see Figure 4.The urinary 8-epi-PGF2a in patients with HC tends to increase faster reaching a maximum after already 5 days as compared to the other two groups (14 and 2 1days, respectively).
been reported by Morrow’s group.19 The increase after restarting smoking is most pronounced with urinary and plasma values. This is similar to the behaviour at quitting. While hypercholesterolemia is associated with increased
Prostaglandins, Leukotrienes and Essential FattyAcids (2001) 64(6), 307^310
310
Chehne et al.
8-epi-PGF2a12 also in this setting, hypertension does not significantly affect the respective values. 15-hydroxyperoxy-arachidonic acid formed during in vivo oxidation injury is a potent inhibitor of PGI2synthesis.20 Furthermore, the other most important endothelial mediator, nitric oxide, is readily transformed by free radicals into peroxynitrite. Vascular 8-epiPGF2a,8,9,12 apparently due to the on-site modification of LDL is a reliable indicator of atherogenicity which has been studied in human and experimental animal vascular tissue. This ratio (8-epi-PGF2a/PGI2) showed a good correlation8,12 to the risk factors and in particular to cigarette smoking and hyperlipidemia. 8-epi-PGF2a is a potent vasoconstrictor which has been demonstrated in coronary arteries21 and human lymphatics.22 It is a mitogen23 and a stimulator of atherogenic mediators.24 It induces shape-change but has a very mild proaggregatory action25 only. 8-epi-PGF2a is also released from human platelets not depending on the antioxidant status and the respective action of a cyclooxygenase blockade. Whether this release per se is affected by cigarette smoking has not been studied so far. Our results indicate that after only a few days after restarting of smoking IP as an indicator of in vivo oxidation injury are significantly enhanced, while after quitting smoking they are rapidly decreasing. This implies that more LDL is modified when people are smoking reflecting a significant in vivo atherogenic potential of LDL. The value of IP-follow-up to monitor smoking behaviour as well as to assess in vivo oxidation injury on a routine base still needs to be elucidated.
ACKNOWLEDGEMENT The valuable help of Eva Unger in preparing and typing the manuscript is gratefully acknowledged.
REFERENCES 1. Krupski W. C. The peripheral vascular consequence of smoking. Ann Vasc Surg 1991; 5: 91–95. 2. Ahmed S. S., Moschos C. B., Lyons M. M., Oldewurtel H. A., Coumbis R. J., Regan T. J. Cardiovascular effects of long-term cigarette smoking and nicotine administration. Am J Cardiol 1976; 37: 33–40. 3. Miettinen O. S., Neff R. K., Jick H. Cigarette smoking and nonfatal myocardial infarction: rate ratio in relation to age, sex and predisposing conditions. Am J Epidemiol 1976; 103: 30–36. 4. Scheffler E., Wirest E., Woehrle J., Otto I., Schulz I., Huber L. Smoking influences the atherogenic potential of low-density lipoprotein. Clin Invest 1992; 70: 263–265. 5. Steinberg D., Parthasarathy S., Carew T. E., Khoo J. C., Witztum J. L. Beyond cholesterol; modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989; 320: 915–924. 6. Steinberg D. Low-density lipoprotein oxidation and its pathobiological significance. J Biol Chem 1997; 272: 2063–2066.
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Prostaglandins, Leukotrienes and Essential FattyAcids (2001) 64(6), 307^310
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