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Antioxidants, dietary fat saturation, lipoprotein oxidation and atherogenesis
EDITORIAL COMMENTS
8.
9.
10.
11. 12. 13. 14.
93-3095 ). Bethesda, MD, National Heart, Lung and Blood Institute, 1993 PDAY Research Group. Relationship of atherosclerosis in young men to serum lipoprotein cholesterol concentrations and smoking. A preliminary report from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. JAMA 1990; 264:3018 Weidman W, Kwiterovich P Jr, Jesse MJ, Nugent E. Diet in the healthy child. Task Force Committee of the Nutrition Committee and the Cardiovascular Disease in the Young Council of the American Heart Association. Circulation 1983; 67:1411A Eaker ED, Castelli WP. Coronary heart disease and its risk factors among women in the Framingham Study. In: Eaker ED, Packard B, Wenger NK, Clarkson TB, Tyroler HA, eds. Coronary heart disease in women. New York, Haymarket Doyma Inc., 1987:122 Millar JS, Lichtenstein AH, Cuchel M, et al. Impact of age on the metabolism of VLDL, IDL, and LDL apolipoprotein B-100 in men. J Lipid Res 1995;36:1155 LaRosa JC, Applegate W, Crouse JR, III et al. Cholesterol lowering in the elderly. Results of the Cholesterol Reduction in Seniors Program (CRISP) Pilot Study. Arch Intern Med 1994; 154:529 Yano K, Reed DM, Curb JD, Hankin JH, Albers JJ. Biological and dietary correlates of plasma lipids and lipoproteins among elderly Japanese men in Hawaii. Arteriosclerosis 1986;6:422 Wood PD, Stefanick ML, Williams PT, Haskell WL. The effects on plasma lipoproteins of a prudent weight-reducing diet, with or
377
15. 16.
17. 18. 19. 20.
21.
without exercise, in overweight men and women. N Engl J Med 1991; 325:461 Hooper PL, Garry PJ, Goodwin JS, Hooper EM, Leonard AG. High-density lipoprotein-cholesterol and diet in a healthy elderly population. J Am Coil Nutr 1982; 1:337 Katzel LI, Bleecker ER, Colman EG, et al. Effects of weight loss vs. aerobic exercise training on risk factors for coronary disease in healthy, obese, middle aged and older men. A randomized controlled trial. JAMA 1995;274:1915 Johnson CL, Rifkind BM, Sempos CT, et al. Declining serum total cholesterol levels among US adults. The National Health and Nutrition Examination Surveys. JAMA 1993;269:3002 Benfante R, Reed D. Is elevated serum cholesterol level a risk factor for coronary heart disease in the elderly? JAMA 1990;263:393 Corti M-C, Guralnik JM, Salive ME, et al. HDL cholesterol predicts coronary heart disease mortality in older persons. JAMA 1995;274:539 Zimetbaum P, Frishman WH, Ooi WL, et al. Plasma lipids and lipoproteins and the incidence of cardiovascular disease in the very elderly. The Bronx Aging Study. Arterioscler Thromb 1992; 12:416 Krumholz HM, Seeman TE, Merrill SS, et al. Lack of association between cholesterol and coronary heart disease mortality and morbidity and all-cause mortality in persons older than 70 years. JAMA 1994; 272:1335
22. Nutrition and Your Health: Dietary Guidelines for Americans, 4th Edition. Home and Garden Bulletin 232. US Department of Agriculture and US Department of Health and Human Services, 1995.
Antioxidants, Dietary Fat Saturation, Lipoprotein Oxidation and Atherogenesis The clinical sequelae of atherosclerosis, coronary heart disease, stroke, and peripheral vascular disease are the leading causes of morbidity and mortality in the United States. ~ Some inter-individual variation in atherosclerosis-related diseases can be explained by a collection of "risk factors" including plasma and lipoprotein cholesterol concentrations, blood pressure, and smoking status. 2 However, a significant part of the variation in risk of atherosclerosis-related diseases remains unexplained by known risk factors, suggesting that other, as yet undetermined, factors influence atherogenesis and clinical cardiovascular disease. There is much interest in the hypothesis that intra-arterial oxidation of lipoproteins such as low-density lipoprotein ( L D L ) contributes to the unexplained variation in risk of atherosclerosis-related diseases. Since several dietary components, including antioxidants and dietary fat saturation, influence atherosclerosis, it is of interest to consider how these studies relate to the oxidation hypothesis. Dietary 3 and pharmacologic 4'5 antioxidants inhibit atherosclerosis in experimental animals. Many 6-a but not other 9 studies in human individuals also suggest that increased intake 6'7 or increased serum or plasma levels 8 of dietary antioxidants are associated with decreased incidence 7 and mortality 6'8 from cardiovascular disease. The oxidation hypothesis provides a
ready explanation for these observations. Intra-arterial oxidation of LDL could promote the entry of monocytes into an artery, the conversion of tissue macrophages to foam cells, and have yet other effects expected to promote atherogenesis. I° In vivo metabolic studies also support the idea that antioxidants inhibit atherosclerosis in part by decreasing intra-arterial oxidation of LDL. 4 Some studies found that antioxidant treatment reduced both the susceptibility of LDL to in vitro lipid peroxidation and atherosclerosis, s Other studies found that treatment with some antioxidants did not affect atherosclerosis yet reduced the susceptibility of LDL to in vitro lipid peroxidation, suggesting that a certain threshold of inhibition of oxidation may be required to inhibit atherosclerosis. I1 In addition, there is evidence that antioxidants could influence atherosclerosis by means independent of effects on lipoprotein oxidation. Intimal smooth muscle cell proliferation and accumulation are characteristic features of atherosclerotic lesions.12 Experiments in culture suggest that the antioxidant vitamin E decreases the mitogenic effects of oxidized LDL 13 and platelet-derived growth factor ~4on smooth muscle cells. In this way, antioxidants couid prevent proliferation and accumulation of intimal smooth muscle cells, exactly what has been observed in experimental animals. ~3'14Reduced smooth muscle cell pro-
378 liferation could alter the arterial extracellular matrix 1~and thus cholesterol accumulation in macrophages secondary to influencing macrophage uptake of LDL-extracellular matrix complexes.16 In contrast, available data for fatty acid saturation do not appear consistent with the oxidation hypothesis. Feeding polyunsaturated fat increases the susceptibility of LDL to in vitro lipid peroxidation compared with monounsaturated fat while feeding diets enriched in monounsaturated and saturated fat results in similar susceptibility of LDL to in vitro lipid peroxidation. 17The oxidation hypothesis would then predict that polyunsaturated fat promotes atherosclerosis compared with monounsaturated fat and saturated fat. In contrast, studies in experimental animalslS show that polyunsaturated fat reduces atherosclerosis compared with saturated fat. In addition, clinical trials have shown that decreasing the proportion of dietary fat that is saturated lowers morbidity and mortality due to cardiovascular disease. 19 The relative effects of monounsaturated fat and polyunsaturated fat are less clear. One study found polyunsaturated fat to reduce atherosclerosis compared with monounsaturated fat is while another study reported the opposite resuit, 20although the difference was not significant. No clinical trials have compared the relative effects of monounsaturated fat and polyunsaturated fat on cardiovascular disease, although one study reported that carotid artery thickness in human individuals was positively related to monounsaturated fat and inversely related to polyunsaturated fat.21 If the oxidation hypothesis is correct, one would have to postulate that effects other than those on lipid peroxidation contribute to mechanism(s) by which dietary fat saturation influences atherosclerosis. In support of this, considerable data suggest that the influence of dietary fat quantity and saturation on atherosclerosis and mortality due to cardiovascular disease is mediated in part by affects on plasma 18'19and LDL cholesterol concentrations,t8'22However, effects on plasma lipids and lipoproteins can explain only part of the increased progression of coronary artery disease associated with higher amounts of dietary total and saturated fat. 22 This suggests that fatty acids may contribute to atherosclerosis and cardiovascular disease in other ways. Such mechanism(s) may include alterations in cellular function, 23 which may be related to changes in cellular membrane fatty acid composition.24 Dietary fatty acid saturation m~y also influence cellular cholesterol balance via effects on 1 ) delivery of cholesterol to arterial cells by metabolism of LDL secondary to influencing interaction of LDL of altered fatty acid composition 17 with arterial proteoglycans, 25 and 2) high-density lipoprotein (HDL) fatty acid composition, which alters the ability of HDL to remove cholesterol from arterial cells.26 How can one reconcile the data for dietary fat saturation and dietary antioxidants with the oxidation hypothesis and move forward to designing optimum diets for prevention of atherosclerosis-related diseases? Overall, the data suggest that salubrious effects of polyunsaturated fatty acids on plasma and lipoprotein concentrations and on certain aspects of cellular function outweigh deleterious effects secondary to promotion of lipid peroxidation. In comparison, harmful effects of saturated fatty acids on plasma lipoprotein concentrations and certain aspects of cellular function exceed the beneficial effects of reduced lipid peroxidation. If this is indeed the case, perhaps an optimum diet to inhibit atherosclerosis and clinical cardiovascular disease would be one enriched in polyunsaturated fatty acids and containing a wide variety of dietary antioxidants (ideally obtained from foods, since not all potentially beneficial dietary antioxidants have been identified6) in concentrations sufficient to prevent intra-arterial oxidation of lipoproteins. Further investigation will be required to establish the composition of such a diet, which might be particularly beneficial for indi-
EDITORIAL COMMENTS viduals with higher levels of plasma cholesterol who are at increased risk of cardiovascular disease. DAWN C, SCHWENKE, PHD Department of Pathology Bowman Gray School of Medicine Wake Forest University Winston-Salem, North Carolina, USA REFERENCES 1. Levy RI. Declining mortalityin coronary heart disease. Arteriosclerosis 1981;1:312 2. Seidel D, Cremer P, Nagel D. Significance of risk factors in the prediction of atherosclerosis. Atheroscler Rev 1991;23:243 3. W6jcicki J, R6zewicka L, Barcew-WiszniewskaB, et al. Effect of selenium and vitamin E on the development of experimental atherosclerosis in rabbits. Atherosclerosis 1991;87:9 4. Carew TE, Schwenke DC, Steinberg D. Antiatherogeniceffect of probucol unrelated to its hypocholesterolemiceffect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-richfatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Proc Natl Acad Sci USA 1987;84:7725 5. Sasahara M, Raines EW, Chait A, et al. Inhibition of hypercholesterolemia-inducedatherosclerosis in the nonhuman primate by probucol .1. Is the extent of atherosclerosis related to resistance of LDL to oxidation? J Clin Invest 1994;94:155 6. Knekt P, Reunanen A, Jarvinen R, et al. Antioxidantvitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol 1994;139:1180 7. Katsouyanni K, Skalkidis Y, Petridou E, et al. Diet and peripheral arterial occlusive disease: The role of poly-, mono-, and saturated fatty acids. Am J Epidemiol 1991;133:24 8. Gey KF, Puska P, Jordan P, Moser UK. Inverse correlationbetween plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Am J Clin Nutr 1991;53:$326 9. The alpha-tocopherol,beta carotene cancer prevention study group. Effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029 10. Witztum JL, Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest 1991;88:1785 11. Fruebis J, Steinberg D, Dresel HA, Carew TE. A comparison of the antiatherogeniceffects of probucol and of a structural analogue of probucol in low density lipoprotein receptor-deficientrabbits. J Clin Invest 1994;94:392 12. Stary HC, Chandler AB, Glagov S, et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committeeon Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1994;89:2462 13. Lafont AM, Chai YC, Cornhill JF, et al. Effect of alpha-tocopherol on restenosis after angiopiasty in a model of experimental atherosclerosis. J Clin Invest 1995;95:1018 14. Konneh MK, Rutherford C, Li SR, Anggard EE, Ferns GAA. Vitamin E inhibits the intimal response to balloon catheter injury in the carotid artery of the cholesterol-fed rat. Atherosclerosis 1995; 113:29 15. Williams SP, Mason RM. Modulation of proteoglycan synthesis by bovine vascular smooth muscle cells during cellular proliferation and treatment with heparin. Arch Biochem Biophys 1991;287:386 16. VijayagopalP, Srinivasan SR, Xu JH, et al. Lipoprotein-proteoglycan complexes induce continued cholesteryl ester accumulation in foam cells from rabbit atherosclerotic lesions. J Clin Invest 1993;91:1011 17. Thomas MJ, Thornburg T, Manning J, Hooper K, Rudel LL. Fatty acid composition of low-density lipoprotein influencesits susceptibility to autoxidation. Biochemistry 1994;33:1828 18. RudelLL, Parks JS, Sawyer JK. Comparedwith dietary monounsaturated and saturated fat, polyunsaturatedfat protects African green monkeys from coronary artery atherosclerosis. ArteriosclerThromb Vase Biol 1995;15:2101 19. Hjermann I, Holme I, Velve Byte K, Leren P. Effect of diet and smoking intervention on the incidence of coronary heart disease.
EDITORIAL COMMENTS
20. 21. 22. 23.
Report from the Oslo Study Group of a randomised trial in healthy men. Lancet 1981;2:1303 Leth-Espensen P, Stender S, Ravn H, Kjeldsen K. Antiatherogenic effect of olive and corn oils in cholesterol-fed rabbits with the same plasma cholesterol levels. Arteriosclerosis 1988;8:281 Tell GS, Evans GW, Folsom AR, et al. Dietary fat intake and carotid artery wall thickness: The Atherosclerosis Risk in Communities (ARIC) Study. Am J Epidemiol 1994; 139:979 Watts GF, Jackson P, Mandalia S, et al. Nutrient intake and progression of coronary artery disease. Am J Cardiol 1994;73:328 Hodgkin DD, Boucek RJ, Purdy RE, et al. Dietary lipids modify
379 receptor- and non-receptor-dependent components of a~-adrenoceptor-mediated contraction. Am J Physiol 1991 ;261 :R1465 24. Berlin E, Shapiro SG, Kliman PG. Influence of saturated and unsaturated fats on platelet fatty acids in cholesterol-fed rabbits. Atherosclerosis 1987;63:85 25. Manning JM, Gebre AK, Edwards LI, et al. Dietary polyunsaturated fat decreases interaction between low density lipoproteins and arterial proteoglycans. Lipids 1994;29:635 26. Davidson WS, Gillotte KL, Lund-Katz S, et al. The effect of high density lipoprotein phospholipid acyl chain composition on the efflux of cellular free cholesterol. J Biol Chem 1995;270:5882
8.
9.
10.
11. 12. 13. 14.
93-3095 ). Bethesda, MD, National Heart, Lung and Blood Institute, 1993 PDAY Research Group. Relationship of atherosclerosis in young men to serum lipoprotein cholesterol concentrations and smoking. A preliminary report from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. JAMA 1990; 264:3018 Weidman W, Kwiterovich P Jr, Jesse MJ, Nugent E. Diet in the healthy child. Task Force Committee of the Nutrition Committee and the Cardiovascular Disease in the Young Council of the American Heart Association. Circulation 1983; 67:1411A Eaker ED, Castelli WP. Coronary heart disease and its risk factors among women in the Framingham Study. In: Eaker ED, Packard B, Wenger NK, Clarkson TB, Tyroler HA, eds. Coronary heart disease in women. New York, Haymarket Doyma Inc., 1987:122 Millar JS, Lichtenstein AH, Cuchel M, et al. Impact of age on the metabolism of VLDL, IDL, and LDL apolipoprotein B-100 in men. J Lipid Res 1995;36:1155 LaRosa JC, Applegate W, Crouse JR, III et al. Cholesterol lowering in the elderly. Results of the Cholesterol Reduction in Seniors Program (CRISP) Pilot Study. Arch Intern Med 1994; 154:529 Yano K, Reed DM, Curb JD, Hankin JH, Albers JJ. Biological and dietary correlates of plasma lipids and lipoproteins among elderly Japanese men in Hawaii. Arteriosclerosis 1986;6:422 Wood PD, Stefanick ML, Williams PT, Haskell WL. The effects on plasma lipoproteins of a prudent weight-reducing diet, with or
377
15. 16.
17. 18. 19. 20.
21.
without exercise, in overweight men and women. N Engl J Med 1991; 325:461 Hooper PL, Garry PJ, Goodwin JS, Hooper EM, Leonard AG. High-density lipoprotein-cholesterol and diet in a healthy elderly population. J Am Coil Nutr 1982; 1:337 Katzel LI, Bleecker ER, Colman EG, et al. Effects of weight loss vs. aerobic exercise training on risk factors for coronary disease in healthy, obese, middle aged and older men. A randomized controlled trial. JAMA 1995;274:1915 Johnson CL, Rifkind BM, Sempos CT, et al. Declining serum total cholesterol levels among US adults. The National Health and Nutrition Examination Surveys. JAMA 1993;269:3002 Benfante R, Reed D. Is elevated serum cholesterol level a risk factor for coronary heart disease in the elderly? JAMA 1990;263:393 Corti M-C, Guralnik JM, Salive ME, et al. HDL cholesterol predicts coronary heart disease mortality in older persons. JAMA 1995;274:539 Zimetbaum P, Frishman WH, Ooi WL, et al. Plasma lipids and lipoproteins and the incidence of cardiovascular disease in the very elderly. The Bronx Aging Study. Arterioscler Thromb 1992; 12:416 Krumholz HM, Seeman TE, Merrill SS, et al. Lack of association between cholesterol and coronary heart disease mortality and morbidity and all-cause mortality in persons older than 70 years. JAMA 1994; 272:1335
22. Nutrition and Your Health: Dietary Guidelines for Americans, 4th Edition. Home and Garden Bulletin 232. US Department of Agriculture and US Department of Health and Human Services, 1995.
Antioxidants, Dietary Fat Saturation, Lipoprotein Oxidation and Atherogenesis The clinical sequelae of atherosclerosis, coronary heart disease, stroke, and peripheral vascular disease are the leading causes of morbidity and mortality in the United States. ~ Some inter-individual variation in atherosclerosis-related diseases can be explained by a collection of "risk factors" including plasma and lipoprotein cholesterol concentrations, blood pressure, and smoking status. 2 However, a significant part of the variation in risk of atherosclerosis-related diseases remains unexplained by known risk factors, suggesting that other, as yet undetermined, factors influence atherogenesis and clinical cardiovascular disease. There is much interest in the hypothesis that intra-arterial oxidation of lipoproteins such as low-density lipoprotein ( L D L ) contributes to the unexplained variation in risk of atherosclerosis-related diseases. Since several dietary components, including antioxidants and dietary fat saturation, influence atherosclerosis, it is of interest to consider how these studies relate to the oxidation hypothesis. Dietary 3 and pharmacologic 4'5 antioxidants inhibit atherosclerosis in experimental animals. Many 6-a but not other 9 studies in human individuals also suggest that increased intake 6'7 or increased serum or plasma levels 8 of dietary antioxidants are associated with decreased incidence 7 and mortality 6'8 from cardiovascular disease. The oxidation hypothesis provides a
ready explanation for these observations. Intra-arterial oxidation of LDL could promote the entry of monocytes into an artery, the conversion of tissue macrophages to foam cells, and have yet other effects expected to promote atherogenesis. I° In vivo metabolic studies also support the idea that antioxidants inhibit atherosclerosis in part by decreasing intra-arterial oxidation of LDL. 4 Some studies found that antioxidant treatment reduced both the susceptibility of LDL to in vitro lipid peroxidation and atherosclerosis, s Other studies found that treatment with some antioxidants did not affect atherosclerosis yet reduced the susceptibility of LDL to in vitro lipid peroxidation, suggesting that a certain threshold of inhibition of oxidation may be required to inhibit atherosclerosis. I1 In addition, there is evidence that antioxidants could influence atherosclerosis by means independent of effects on lipoprotein oxidation. Intimal smooth muscle cell proliferation and accumulation are characteristic features of atherosclerotic lesions.12 Experiments in culture suggest that the antioxidant vitamin E decreases the mitogenic effects of oxidized LDL 13 and platelet-derived growth factor ~4on smooth muscle cells. In this way, antioxidants couid prevent proliferation and accumulation of intimal smooth muscle cells, exactly what has been observed in experimental animals. ~3'14Reduced smooth muscle cell pro-
378 liferation could alter the arterial extracellular matrix 1~and thus cholesterol accumulation in macrophages secondary to influencing macrophage uptake of LDL-extracellular matrix complexes.16 In contrast, available data for fatty acid saturation do not appear consistent with the oxidation hypothesis. Feeding polyunsaturated fat increases the susceptibility of LDL to in vitro lipid peroxidation compared with monounsaturated fat while feeding diets enriched in monounsaturated and saturated fat results in similar susceptibility of LDL to in vitro lipid peroxidation. 17The oxidation hypothesis would then predict that polyunsaturated fat promotes atherosclerosis compared with monounsaturated fat and saturated fat. In contrast, studies in experimental animalslS show that polyunsaturated fat reduces atherosclerosis compared with saturated fat. In addition, clinical trials have shown that decreasing the proportion of dietary fat that is saturated lowers morbidity and mortality due to cardiovascular disease. 19 The relative effects of monounsaturated fat and polyunsaturated fat are less clear. One study found polyunsaturated fat to reduce atherosclerosis compared with monounsaturated fat is while another study reported the opposite resuit, 20although the difference was not significant. No clinical trials have compared the relative effects of monounsaturated fat and polyunsaturated fat on cardiovascular disease, although one study reported that carotid artery thickness in human individuals was positively related to monounsaturated fat and inversely related to polyunsaturated fat.21 If the oxidation hypothesis is correct, one would have to postulate that effects other than those on lipid peroxidation contribute to mechanism(s) by which dietary fat saturation influences atherosclerosis. In support of this, considerable data suggest that the influence of dietary fat quantity and saturation on atherosclerosis and mortality due to cardiovascular disease is mediated in part by affects on plasma 18'19and LDL cholesterol concentrations,t8'22However, effects on plasma lipids and lipoproteins can explain only part of the increased progression of coronary artery disease associated with higher amounts of dietary total and saturated fat. 22 This suggests that fatty acids may contribute to atherosclerosis and cardiovascular disease in other ways. Such mechanism(s) may include alterations in cellular function, 23 which may be related to changes in cellular membrane fatty acid composition.24 Dietary fatty acid saturation m~y also influence cellular cholesterol balance via effects on 1 ) delivery of cholesterol to arterial cells by metabolism of LDL secondary to influencing interaction of LDL of altered fatty acid composition 17 with arterial proteoglycans, 25 and 2) high-density lipoprotein (HDL) fatty acid composition, which alters the ability of HDL to remove cholesterol from arterial cells.26 How can one reconcile the data for dietary fat saturation and dietary antioxidants with the oxidation hypothesis and move forward to designing optimum diets for prevention of atherosclerosis-related diseases? Overall, the data suggest that salubrious effects of polyunsaturated fatty acids on plasma and lipoprotein concentrations and on certain aspects of cellular function outweigh deleterious effects secondary to promotion of lipid peroxidation. In comparison, harmful effects of saturated fatty acids on plasma lipoprotein concentrations and certain aspects of cellular function exceed the beneficial effects of reduced lipid peroxidation. If this is indeed the case, perhaps an optimum diet to inhibit atherosclerosis and clinical cardiovascular disease would be one enriched in polyunsaturated fatty acids and containing a wide variety of dietary antioxidants (ideally obtained from foods, since not all potentially beneficial dietary antioxidants have been identified6) in concentrations sufficient to prevent intra-arterial oxidation of lipoproteins. Further investigation will be required to establish the composition of such a diet, which might be particularly beneficial for indi-
EDITORIAL COMMENTS viduals with higher levels of plasma cholesterol who are at increased risk of cardiovascular disease. DAWN C, SCHWENKE, PHD Department of Pathology Bowman Gray School of Medicine Wake Forest University Winston-Salem, North Carolina, USA REFERENCES 1. Levy RI. Declining mortalityin coronary heart disease. Arteriosclerosis 1981;1:312 2. Seidel D, Cremer P, Nagel D. Significance of risk factors in the prediction of atherosclerosis. Atheroscler Rev 1991;23:243 3. W6jcicki J, R6zewicka L, Barcew-WiszniewskaB, et al. Effect of selenium and vitamin E on the development of experimental atherosclerosis in rabbits. Atherosclerosis 1991;87:9 4. Carew TE, Schwenke DC, Steinberg D. Antiatherogeniceffect of probucol unrelated to its hypocholesterolemiceffect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-richfatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Proc Natl Acad Sci USA 1987;84:7725 5. Sasahara M, Raines EW, Chait A, et al. Inhibition of hypercholesterolemia-inducedatherosclerosis in the nonhuman primate by probucol .1. Is the extent of atherosclerosis related to resistance of LDL to oxidation? J Clin Invest 1994;94:155 6. Knekt P, Reunanen A, Jarvinen R, et al. Antioxidantvitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol 1994;139:1180 7. Katsouyanni K, Skalkidis Y, Petridou E, et al. Diet and peripheral arterial occlusive disease: The role of poly-, mono-, and saturated fatty acids. Am J Epidemiol 1991;133:24 8. Gey KF, Puska P, Jordan P, Moser UK. Inverse correlationbetween plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Am J Clin Nutr 1991;53:$326 9. The alpha-tocopherol,beta carotene cancer prevention study group. Effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029 10. Witztum JL, Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest 1991;88:1785 11. Fruebis J, Steinberg D, Dresel HA, Carew TE. A comparison of the antiatherogeniceffects of probucol and of a structural analogue of probucol in low density lipoprotein receptor-deficientrabbits. J Clin Invest 1994;94:392 12. Stary HC, Chandler AB, Glagov S, et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committeeon Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1994;89:2462 13. Lafont AM, Chai YC, Cornhill JF, et al. Effect of alpha-tocopherol on restenosis after angiopiasty in a model of experimental atherosclerosis. J Clin Invest 1995;95:1018 14. Konneh MK, Rutherford C, Li SR, Anggard EE, Ferns GAA. Vitamin E inhibits the intimal response to balloon catheter injury in the carotid artery of the cholesterol-fed rat. Atherosclerosis 1995; 113:29 15. Williams SP, Mason RM. Modulation of proteoglycan synthesis by bovine vascular smooth muscle cells during cellular proliferation and treatment with heparin. Arch Biochem Biophys 1991;287:386 16. VijayagopalP, Srinivasan SR, Xu JH, et al. Lipoprotein-proteoglycan complexes induce continued cholesteryl ester accumulation in foam cells from rabbit atherosclerotic lesions. J Clin Invest 1993;91:1011 17. Thomas MJ, Thornburg T, Manning J, Hooper K, Rudel LL. Fatty acid composition of low-density lipoprotein influencesits susceptibility to autoxidation. Biochemistry 1994;33:1828 18. RudelLL, Parks JS, Sawyer JK. Comparedwith dietary monounsaturated and saturated fat, polyunsaturatedfat protects African green monkeys from coronary artery atherosclerosis. ArteriosclerThromb Vase Biol 1995;15:2101 19. Hjermann I, Holme I, Velve Byte K, Leren P. Effect of diet and smoking intervention on the incidence of coronary heart disease.
EDITORIAL COMMENTS
20. 21. 22. 23.
Report from the Oslo Study Group of a randomised trial in healthy men. Lancet 1981;2:1303 Leth-Espensen P, Stender S, Ravn H, Kjeldsen K. Antiatherogenic effect of olive and corn oils in cholesterol-fed rabbits with the same plasma cholesterol levels. Arteriosclerosis 1988;8:281 Tell GS, Evans GW, Folsom AR, et al. Dietary fat intake and carotid artery wall thickness: The Atherosclerosis Risk in Communities (ARIC) Study. Am J Epidemiol 1994; 139:979 Watts GF, Jackson P, Mandalia S, et al. Nutrient intake and progression of coronary artery disease. Am J Cardiol 1994;73:328 Hodgkin DD, Boucek RJ, Purdy RE, et al. Dietary lipids modify
379 receptor- and non-receptor-dependent components of a~-adrenoceptor-mediated contraction. Am J Physiol 1991 ;261 :R1465 24. Berlin E, Shapiro SG, Kliman PG. Influence of saturated and unsaturated fats on platelet fatty acids in cholesterol-fed rabbits. Atherosclerosis 1987;63:85 25. Manning JM, Gebre AK, Edwards LI, et al. Dietary polyunsaturated fat decreases interaction between low density lipoproteins and arterial proteoglycans. Lipids 1994;29:635 26. Davidson WS, Gillotte KL, Lund-Katz S, et al. The effect of high density lipoprotein phospholipid acyl chain composition on the efflux of cellular free cholesterol. J Biol Chem 1995;270:5882