биохимия атеросклероза
.pdf
Chapter 22. Modification of Biochemical and Cellular Processes |
483 |
Red wine
↑ HDL |
↑ NO |
↓ ET-1 |
↓ hs-CRP |
Maintenance of endothelial function
↓ Atherosclerosis
FIGURE 22.2. Effect of red wine on maintenance of endothelial function. HDL, highdensity lipoproteins; NO, nitric oxide; ET-1, endothelin-1; hs-CRP, high sensitivity C-reactive protein; ↑, increase; ↓, decrease.
formation, is also reduced by red wine, quercetin, and catechin in atherosclerotic apoE knockout mice [64]. These observations were further verified by treating LDL, isolated from human volunteers, who consumed wine for a period of 2 weeks. Cu2+-induced lipid peroxidation manifested by the formation of lipid peroxides, thiobarbituric acid reaction substances, and conjugated dienes was reduced 72%, 54%, and 46%, respectively in these subjects after red wine consumption [65]. Two possible mechanisms have been proposed; firstly, the phenolic compounds complex with Cu2+ reductase and covert Cu2+ to Cu+, which in turn reduces hydroperoxides; secondly, phenols in wine may act as self-regenerating reducing components [61]. Although grape juice has been reported to inhibit the Cu2+ catalyzed human LDL oxidation in vitro, red wine consumption-induced enhancement of LDL resistance to oxidation in vivo was not mimicked by grape juice consumption [66]. Increased intestinal absorption of flavonoids due to alcohol content of red wine may be the reason for such an effect [67]. In addition, it has been demonstrated that alcohol is a natural stabilizing agent for polyphenolic components in red wine [68] and thus the effectiveness of polyphenols in red wine and grape juice appears to be different. Red wine polyphenols have also been reported to prevent LDL oxidation by reducing oxidative stress in macrophages through inhibition of oxygenases such as NADPH oxidase, 15-lipoxygenase, cytochrome P450, myeloperoxidase as well as by increasing the cellular antioxidants such as glutathione system [69].
484 Harjot K. Saini et al.
Modification of VSMC Proliferation by Red Wine
VSMC proliferation and migration are the critical events associated with the progressive intimal thickening and arterial wall sclerosis [16]. Red wine polyphenols have been shown to inhibit the SMC proliferation and DNA synthesis in rat aortic SMCs [38]. Different mechanisms have been proposed; the potential pathway involves the downregulation of activating transcriptional factor-1 and cAMP response element leading to the decreased expression of cyclin A, a cell cycle regulator in DNA replication at G1/S transition and in the S and G2/M phases [38]. Red wine polyphenol, resveratrol, has been shown to be the major component linked with inhibition of the cell cycle progression at S/G2 phase transition and prevention of VSMC proliferation [70]. Resveratrol-mediated production of reactive oxygen species by binding with DNA and subsequent reduction of Cu2+ to Cu+ has also been suggested as the DNA cleaving effect of resveratrol [71]. Another mechanism involves the downregulation of phosphatidylinositol 3′-kinase and p38 mito- gen-activated protein kinase activity [38]. In addition, red wine polyphenols has been shown to be associated with inhibition of VSMC-mediated migration during atherosclerosis [72]. Inhibition of PDGFβ has also been linked with red wine polyphenol-mediated VSMC proliferation and migration [72]. Furthermore, PDGF-induced overexpression of vascular endothelial growth factor and other growth factors such as α-thrombonin and transforming growth factor-β, which are mainly involved in VSMC proliferation, have been shown to be inhibited by red wine polyphenols [73].
Modification of Inflammation by Red Wine
Moderate amount of red wine has been reported to inhibit the expression of MCP-1, a potent chemoattractant for circulating monocytes, and to cause reduction in neointimal hyperplasia after balloon injury in cholesterol fed rabbits [74]. In addition, red wine prevents the activation of nuclear factor kappa B (NFκB), a transcriptional factor involved in immune and inflammatory response, in peripheral blood mononuclear cells [75]. Furthermore, a significant reduction in the inflammatory mediators of atherosclerosis such as lymphocyte function associated antigen-1, Mac-1, very late activation antigen-4, VCAM-1, ICAM-1, IL-1α, hs-CRP, and fibrogen content was observed in healthy individuals by red wine consumption [51]. Although no effect on serum TNF-α content was observed after red wine polyphenols, TNF-α induced VCAM-1 expression was reduced by polyphenols especially proanthocyanidines in human umbilical endothelial cells leading to reduced adhesion with leukocytes and T-cells [76, 77]. Recent studies have demonstrated that resveratrol in red wine has the capability to reduce TNF-α and lipopolysaccharide stimulated expression of VCAM-1 in HUVEC [78]. This effect of red wine was simulated by N-acetyl cysteine, a known antioxidant, suggesting the involvement of reactive oxygen species in this process [78].
Chapter 22. Modification of Biochemical and Cellular Processes |
485 |
Since VCAM-1 promoter has various binding regions for transcriptional factors such as NFκB and activator protein-1, resveratrol has also been shown to inhibit the activation of these transcriptional factors in addition to VCAM-1
[79].Previous studies have shown that quercetin and resveratrol prove to be effective inhibitors of 5-lipoxygenase pathways, which are known to be involved in the synthesis of leukotriens, powerful mediators of inflammation
[80].Resveratrol also inhibits the release of elastase and β-glucuronidase from neutrophil, which inhibits the expression of β2-integrin as well as Mac-1, and therefore it downregulates the adhesion-dependent thrombogenic functions
[81].From these observations, it emerges that red wine consumption causes the inhibition of LDL oxidation, VSMC proliferation and migration, as well as various inflammatory mediators, which are important targets for impairment of the plaque formation and progression as shown in Figs. 22.3 and 22.4.
Modification of Platelet Aggregation and Thrombosis by Red Wine
Red wine supplementation has been shown to prevent experimental thrombosis in mechanically stenosed canine coronary arteries independent of its alcohol content [82]. Xia et al. [83] have demonstrated that polyphenols are responsible for the antiplatelet aggregation effect of red wine. Keevil et al. [84] have further confirmed the involvement of polyphenols in the inhibition of platelet aggregation as drinking approximately two cups of purple grape juice for 1 week inhibits the platelet aggregation in healthy humans as
Red wine
↓ LDL |
↓ VCAM-1 |
↓ MCP-1 |
↓ Macrophage |
↓ NF-κB |
oxidation |
|
transmigration |
|
|
|
|
|
Impairment of plaque formation
↓ Atherosclerosis
FIGURE 22.3. Effect of red wine on impairment of plaque formation. LDL, lowdensity lipoprotein; VCAM-1, vascular cell adhesion molecule-1; MCP-1, monocyte chemoattractant protein-1; NFκB, nuclear factor kappa B; ↓, decrease.
486 Harjot K. Saini et al.
Red wine
↓ LDL |
↓ SMC |
↓ SMC |
oxidation |
migration |
proliferation |
Attenuation of plaque progression
↓ Atherosclerosis
FIGURE 22.4. Effect of red wine on attenuation of plaque progression. LDL, lowdensity lipoprotein; SMC, smooth muscle cell; ↓, decrease.
determined by whole blood aggregometry with collagen, ADP or thrombin. To further establish whether ethanol or phenolic components of red wine exert inhibitory effect on hemostasis and thrombosis, Wollny et al. [85] treated rats with both of these components. The authors concluded that red wine causes attenuation of hemostatic parameters, such as template bleeding time and platelet adhesion to fibrillar collagen as well as prevents the experimental thrombosis regardless of its alcohol content [85]. In addition, alcohol-free red wine has been shown to be as effective as original wine suggesting that red wine components other than alcohol may be responsible for the observed effects [85]. In vitro experiments have demonstrated that polyphenols such as resveratrol and quercitin have the maximum antiplatelet aggregating effect [86]. Quercitin and resveratrol have also been found to potentiate PGI2 levels by increasing cAMP in platelets, which cause a decrease in cytosolic Ca2+ leading to prevention of platelet aggregation [86]. Resveratrol has also been reported as an inhibitor of cyclooxygenase pathway as it causes a decrease in thromboxane A2 production [87]. In addition, quercetin inhibits lipoxygenase system by impairing 12-hydroxyeicosatetraenoic production. Furthermore, it has been observed that red wine polyphenols inhibit phosphodiesterase, phopsholipase A2 and reduce oxidative stress on thrombocytes [87]. Wolley et al. [85] have demonstrated the involvement of NO in the prevention of experimental thrombosis by red wine polyphenol treatment. It is pointed out that ethanol has no effect on hemostatic parameters, whereas it causes a reduction in experimental thrombosis [85]. These studies indicated that alcohol and nonalcoholic components of red wine have different effects on atherosclerosis
Chapter 22. Modification of Biochemical and Cellular Processes |
487 |
plaque development and progression [85]. On the other hand, Pellegrini et al. [88] in a randomized crossover study have reported that alcoholic content of red wine, unlike nonalcoholic components, causes a decrease in collageninduced platelet aggregation and fibrinogen content suggesting that beneficial effects of red wine on platelet aggregation and haemostatic variables are associated with the alcohol content. Nonetheless, both alcohol and polyphenolic compounds in red wine have antithrombotic properties as the reduction in the levels of tissue factor, von Willebrand factor and factor VII was observed after moderate amounts of alcohol consumption [89] with an increase in tissue plasminogen activator and reduction in plasminogen activator inhibitor antigen-1 after red wine intake [90, 91]. The schematic representation of antithrombotic effect of red wine is given in Fig. 22.5.
Conclusions
From the forgoing discussion, it is evident that we have described the sequence of events associated with the biochemical and cellular processes for the development and progression of atherosclerosis. Various factors such as hypercholesterolemia, oxidative stress, inflammation, endothelial dysfunction, SMC proliferation and migration, platelet activation, and adhesion of monocytes seem to play a critical role in the genesis and progression of atherosclerosis. Although a variety of possible mechanisms have been proposed for the antiatherosclerotic effects of alcoholic and polyphenolic
Red wine
↓ TF, vWF, |
↓ Fibrinogen |
↓ Platelet |
↑ tPA |
factor VII |
|||
|
|
aggregation |
|
Reduction of
thrombosis
↓ Atherosclerosis
FIGURE 22.5. Effect of red wine on reduction of thrombus formation. TF, tissue factor; vWF, von Willebrand factor; tPA, tissue plasminogen activator; ↑, increase; ↓, decrease.
488 Harjot K. Saini et al.
Ethanol
↓ Coagulation |
↓ Platelet |
↓ Thrombosis |
↓ Inflammation |
↑ HDL |
|
aggregation |
|
|
|
↓ Atherosclerosis
FIGURE 22.6. Effect of red wine ethanol on different mediators of atherosclerosis. ↑, increase; ↓, decrease.
components of red wine [92, 93] as shown in Figs. 22.6 and 22.7, the conclusions drawn from different studies vary from each other. The differences in the amount of wine consumption, experimental conditions, and varieties of wines in terms of the type of grapes, the region in which grown or the method of cultivation may be the reason for such discrepancies [94]. Because of the multifactorial nature of the disease, the results are also influenced by the socioeconomic, genetic, dietary, and environmental factors. Furthermore, American Heart Association Science Advisory Committee has stated that red wine consumption is no more beneficial than moderate amounts of other alcoholic beverages [95]. In fact, the additional beneficial effects due to red wine polyphenolic components can be achieved by grape juice consumption [95]. Therefore, the question related to the therapeutic recommendation of red wine consumption remains unanswered and still a
Polyphenolic components
↓ Thrombosis |
↑ Endothelial |
↓ SMC |
↓ Inflammation |
↓ LDL |
|
oxidation |
|||||
function |
proliferation |
||||
|
|
|
↓ Atherosclerosis
FIGURE 22.7. Effect of red wine polyphenolic components on different mediators of atherosclerosis. ↑, increase; ↓, decrease.
Chapter 22. Modification of Biochemical and Cellular Processes |
489 |
matter of discussion between the patient and the physician. Further studies focusing on differentiating the effects of types of alcoholic beverages, identifying and adjustment of the confounding factors, as well as assessing the pattern of consumption, may provide definitive evidence of the antiatherosclerotic potential of red wine.
Acknowledgments: The work reported in the article was supported by a grant from the Canadian Institutes of Health Research. HKS is a predoctoral fellow of the Heart and Stroke Foundation of Canada. SKC holds a New Investigator Award from the Canadian Institutes of Health Research.
References
1.Murray CJ, Lopez AD: Alternative projections of mortality and disability by cause 1990–2020: Global burden of disease Study. Lancet 349:1498–1504, 1997.
2.Neaton JD, Wentworth D: Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial Research Group. Arch Intern Med 152: 56–64, 1992.
3.Kannel WB, Wilson PW: An update on coronary risk factors. Med Clin North Am 79: 951–971, 1995.
4.LaRosa JC, He J, Vupputuri S: Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 282: 2340–2346, 1999.
5.National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106: 3143–3421, 2002.
6.Grundy SM: Alternative approaches to cholesterol-lowering therapy. Am J Cardiol
90:1135–1138, 2002.
7.Lipid Research Clinics Program. JAMA 252: 2545–2448, 1984.
8.Davignon J: Beneficial cardiovascular pleiotropic effects of statins. Circulation
109:39–43, 2004.
9.Renaud S, de Lorgeril M: Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 339: 1523–1526, 1992.
10.de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N: Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation 99: 779–785, 1999.
11.van de Wiel A, van Golde PH, Hart HC: Blessings of the grape. Eur J Intern Med 12: 484–489, 2001.
12.Waterhouse AL: Wine phenolics. Ann NY Acad Sci 957: 21–36, 2002.
13.Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW: A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 92: 1355–1374, 1995.
490Harjot K. Saini et al.
14.Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM: Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 20: 1262–1275, 2000.
15.Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA, Watson AD, Lusis AJ: Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation 91: 2488–2496, 1995.
16.Ross R, Glomset JA: Atherosclerosis and the arterial smooth muscle cell: Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science 180: 1332–1339, 1973.
17.Ross R: Atherosclerosis—an inflammatory disease. N Engl J Med 340: 115–126, 1999.
18.Matsuoka H: Endothelial dysfunction associated with oxidative stress in human. Diabetes Res Clin Pract 54: 65–72, 2001.
19.da Luz PL, Coimbra SR: Wine, alcohol and atherosclerosis: clinical evidences and mechanisms. Braz J Med Biol Res 37: 1275–1295, 2004.
20.Eriksson EE: Mechanisms of leukocyte recruitment to atherosclerotic lesions: future prospects. Curr Opin Lipidol 15: 553–558, 2004.
21.Osterud B, Bjorklid E: Role of monocytes in atherogenesis. Physiol Rev 83: 1069–1112, 2003.
22.Holvoet P, Collen D: Oxidation of low density lipoproteins in the pathogenesis of atherosclerosis. Atherosclerosis 137: 33–38, 1998.
23.Chisolm GM, Steinberg D: The oxidative modification hypothesis of atherogenesis: an overview. Free Radic Biol Med 28: 1815–1826, 2000.
24.Lindner A, Charra B, Sherrard DJ, Scribner BH: Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 290: 697–701, 1974.
25.Saini HK, Arneja AS, Dhalla NS: Role of cholesterol in cardiovascular dysfunction. Can J Cardiol 20: 333–346, 2004.
26.Xu YJ, Aziz OA, Bhugra P, Arneja AS, Mendis MR, Dhalla NS: Potential role of lysophosphatidic acid in hypertension and atherosclerosis. Can J Cardiol 19: 1525–1536, 2003.
27.Xu YJ, Rathi SS, Chapman DC, Arneja AS, Dhalla NS: Mechanisms of lysophosphatidic acid-induced DNA synthesis in vascular smooth muscle cells. J Cardiovasc Pharmacol 41: 381–387, 2003.
28.Wolfbauer G, Glick JM, Minor LK, Rothblat GH: Development of the smooth muscle foam cell: uptake of macrophage lipid inclusions. Proc Natl Acad Sci USA 83: 7760–7764, 1986.
29.Shah PK: Pathophysiology of plaque rupture and the concept of plaque stabilization. Cardiol Clin 21: 303–314, 2003.
30.Moncada S, Palmer RM, Higgs EA: Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43: 109–142, 1991.
31.Zeiher AM, Fisslthaler B, Schray-Utz B, Busse R: Nitric oxide modulates the expression of monocyte chemoattractant protein 1 in cultured human endothelial cells. Circ Res 76: 980–986, 1995.
32.Gauthier TW, Scalia R, Murohara T, Guo JP, Lefer AM: Nitric oxide protects against leukocyte–endothelium interactions in the early stages of hypercholesterolemia. Arterioscler Thromb Vasc Biol 15: 1652–1659, 1995.
33.Forstermann U, Nakane M, Tracey WR, Pollock JS: Isoforms of nitric oxide synthase: functions in the cardiovascular system. Eur Heart J 14: 10–15, 1993.
Chapter 22. Modification of Biochemical and Cellular Processes |
491 |
34.Garg UC, Hassid A: Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 83: 1774–1777, 1989.
35.Radomski MW, Palmer RM, Moncada S: The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium. Biochem Biophys Res Commun 148:1482–1489, 1987.
36.Hirafuji M, Nezu A, Shinoda H, Minami M: Involvement of platelet cyclic GMP but not cyclic AMP suppression in leukocyte-dependent platelet adhesion to endothelial cells induced by platelet-activating factor in vitro. Br J Pharmacol
117:299–304, 1996.
37.Goss SP, Kalyanaraman B, Hogg N: Antioxidant effects of nitric oxide and nitric oxide donor compounds on low-density lipoprotein oxidation. Methods Enzymol 301: 444–453, 1999.
38.Dell’Agli M, Busciala A, Bosisio E: Vascular effects of wine polyphenols. Cardiovasc Res 63: 593–602, 2004.
39.Fitzpatrick DF, Hirschfield SL, Coffey RG: Endothelium-dependent vasorelaxing activity of wine and other grape products. Am J Physiol Heart Circ Physiol
265:H774–H778, 1993.
40.Flesch M, Schwarz A, Bohm M: Effects of red and white wine on endotheliumdependent vasorelaxation of rat aorta and human coronary arteries. Am J Physiol Heart Circ Physiol 275: H1183–H1190, 1998.
41.Andriambeloson E, Kleschyov AL, Muller B, Beretz A, Stoclet JC, Andriantsitohaina R: Nitric oxide production and endothelium-dependent vasorelaxation induced by wine polyphenols in rat aorta. Br J Pharmacol 120: 1053–1058, 1997.
42.Zenebe W, Pechanova O, Andriantsitohaina R: Red wine polyphenols induce vasorelaxation by increased nitric oxide bioactivity. Physiol Res 52: 425–432, 2003.
43.Wallerath T, Poleo D, Li H, Forstermann U: Red wine increases the expression of human endothelial nitric oxide synthase: a mechanism that may contribute to its beneficial cardiovascular effects. J Am Coll Cardiol 41: 471–478, 2003.
44.Wallerath T, Deckert G, Ternes T, Anderson H, Li H, Witte K, Forstermann U: Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation 106: 1652–1658, 2002.
45.Goldberg DM, Yan J, Ng E, Diamandis EP, Karumanchiri A, Soleas G, Waterhouse AL: A global survey of trans-resveratrol concentrations in commercial wines. Am J Enol Viticult 46: 159–165, 1995.
46.Andriambeloson E, Stoclet JC, Andriantsitohaina R: Mechanism of endothelial nitric oxide-dependent vasorelaxation induced by wine polyphenols in rat thoracic aorta. J Cardiovasc Pharmacol 33: 248–254, 1999.
47.Diebolt M, Bucher B, Andriantsitohaina R: Wine polyphenols decrease blood pressure, improve NO vasodilatation, and induce gene expression. Hypertension
38:159–165, 2001.
48.Derek D, Pearson DA, German JB: Endothelial cell basal PGI2 release is stimulated by wine in vitro: one mechanism that may mediate the vasoprotective effects of wine. J Nutr Biochem 8: 647–651, 1997.
49.Ndiaye M, Chataigneau T, Andriantsitohaina R, Stoclet JC, Schini-Kerth VB: Red wine polyphenols cause endothelium-dependent EDHF-mediated relaxations in porcine coronary arteries via a redox-sensitive mechanism. Biochem Biophys Res Commun 310: 371–377, 2003.
492Harjot K. Saini et al.
50.Corder R, Douthwaite JA, Lees DM, Khan NQ, Viseu Dos Santos AC, Wood EG, Carrier MJ: Endothelin-1 synthesis reduced by red wine. Nature 414: 863–864, 2001.
51.Estruch R, Sacanella E, Badia E, Antunez E, Nicolas JM, Fernandez-Sola J, Rotilio D, de Gaetano G, Rubin E, Urbano-Marquez A: Different effects of red wine and gin consumption on inflammatory biomarkers of atherosclerosis: a prospective randomized crossover trial. Effects of wine on inflammatory markers. Atherosclerosis 175: 117–123, 2004
52.Fielding CJ, Fielding PE: Molecular physiology of reverse cholesterol transport. J Lipid Res 36: 211–228, 1995.
53.Parthasarathy S, Barnett J, Fong LG: High-density lipoprotein inhibits the oxidative modification of low-density lipoprotein. Biochim Biophys Acta 1044: 275–283, 1990.
54.Watson AD, Berliner JA, Hama SY, La Du BN, Faull KF, Fogelman AM, Navab
M:Protective effect of high-density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest 96: 2882–2891, 1995.
55.Watson AD, Navab M, Hama SY, Sevanian A, Prescott SM, Stafforini DM, McIntyre TM, Du BN, Fogelman AM, Berliner JA: Effect of platelet activating factor-acetylhydrolase on the formation and action of minimally oxidized low density lipoprotein. J Clin Invest 95: 774–782, 1995.
56.Rajaram OV, Barter PJ: Increases in the particle size of high-density lipoproteins induced by purified lecithin: cholesterol acyltransferase: effect of low-density lipoproteins. Biochim Biophys Acta 877: 406–414, 1986.
57.Christison JK, Rye KA, Stocker R: Exchange of oxidized cholesteryl linoleate between LDL and HDL mediated by cholesteryl ester transfer protein. J Lipid Res 36: 2017–2026, 1995.
58.Araya J, Rodrigo R, Orellana M, Rivera G: Red wine raises plasma HDL and preserves long-chain polyunsaturated fatty acids in rat kidney and erythrocytes. Br J Nutr 86: 189–195, 2001.
59.Perret B, Ruidavets JB, Vieu C, Jaspard B, Cambou JP, Terce F, Collet X: Alcohol consumption is associated with enrichment of high-density lipoprotein particles in polyunsaturated lipids and increased cholesterol esterification rate. Alcohol Clin Exp Res 26: 1134–1140, 2002.
60.Yuhanna IS, Zhu Y, Cox BE, Hahner LD, Osborne-Lawrence S, Lu P, Marcel YL, Anderson RG, Mendelsohn ME, Hobbs HH, Shaul PW: High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase. Nat Med 7: 853–857, 2001.
61.Frankel EN, Kanner J, German JB, Parks E, Kinsella JE: Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine. Lancet 341: 454–457, 1993.
62.Aviram M, Fuhrman B: Wine flavonoids protect against LDL oxidation and atherosclerosis. Ann NY Acad Sci 957:146–161, 2002.
63.Hayek T, Oiknine J, Brook JG, Aviram M: Increased plasma and lipoprotein lipid peroxidation in apo E-deficient mice. Biochem Biophys Res Commun 201: 1567–1574, 1994.
64.Hayek T, Fuhrman B, Vaya J, Rosenblat M, Belinky P, Coleman R, Elis A, Aviram M: Reduced progression of atherosclerosis in apolipoprotein E-deficient mice following consumption of red wine, or its polyphenols quercetin or cate-