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High-Energy Diets, Fatty Acids and Endothelial Cell Function: Implications for Atherosclerosis

Department of Animal Sciences (B.H.), University of Kentucky, Lexington
Department of Surgery (M.T.), University of Kentucky, Lexington
Graduate Centers for Nutritional Sciences and Toxicology (B.H., M.T., C.J.M.), University of Kentucky, Lexington
Department of Medicine, University of Louisville, Louisville (C.J.M.), Kentucky

Address reprint requests to: Bernhard Hennig, PhD, RD, FACN, Cell Nutrition Group, Department of Animal Sciences, College of Agriculture, 204 Funkhouser Building, University of Kentucky, Lexington, KY 40506-0054. E-mail: bhennig{at}pop.uky.edu

	ABSTRACT

TOP ABSTRACT Introduction: Endothelial Cell... Hypertriglyceridemia Is an... Atherosclerosis Is a Major... High LPL Activity Is... Endothelial Cell Dysfunction as... Activation of Transcription... Protection by Selected Nutrients... Conclusion REFERENCES

 
Diets high in fat and/or calories can lead to hypertriglyceridemia and postprandial lipemia and thus are considered a risk factor for the development of atherosclerosis. Plasma chylomicron levels are elevated in humans after consuming a high-fat meal, and hepatic synthesis of VLDL is increased when caloric intake is in excess of body needs. High lipoprotein lipase activity and subsequent hydrolysis of triglyceride-rich lipoproteins may be an important source of elevated concentrations of fatty acid anions in the proximity to the endothelium and hence a major risk factor for atherosclerosis. We have shown that selected fatty acids, as well as lipoprotein lipase-derived remnants of lipoproteins isolated from hypertriglyceridemic subjects, can activate vascular endothelial cells and disrupt endothelial integrity. Our studies suggest that omega-6 fatty acids, and especially linoleic acid, cause endothelial cell dysfunction most markedly as well as can potentiate TNF-mediated endothelial cell injury. We propose that high-energy diets, and especially diets rich in linoleic acid, are atherogenic by contributing to an imbalance in cellular oxidative stress/antioxidant status of the endothelium, which can lead to activation of oxidative stress-responsive transcription factors, inflammatory cytokine production and the expression of adhesion molecules. Our data also suggest that nutrients, which have antioxidant and/or membrane stabilizing properties, can protect endothelial cells. These findings contribute to the understanding of the interactive role of high fat/calorie diets and subsequent hypertriglyceridemia with inflammatory components and nutrients that exhibit antiatherogenic properties in the development of atherosclerosis. Moreover, results from our research further support the concept that high-fat/calorie diets and associated postprandial hypertriglyceridemia are significant risk factors for atherosclerosis.

Key words: high-energy diets, hypertriglyceridemia, postprandial lipemia, fatty acids, endothelial cell dysfunction, atherosclerosis

Key teaching points:

• High-energy nutrition, with subsequent chronic postprandial lipemia and hypertriglyceridemia, is an independent risk factor in the development of atherosclerosis.

• Triglyceride-rich lipoproteins and associated hypertriglyceridemia, as well as high lipoprotein lipase activity, can contribute to excessive fatty acid release in the proximity of the vascular endothelium. This may cause endothelial cell activation, dysfunction and initiate inflammatory events.

• High dietary and serum polyunsaturated fatty acids (e.g., linoleic acid), when insufficiently protected by antioxidants, may cause endothelial cell activation and thus indicate a higher risk of atherosclerosis.

• Certain dietary fats can potentiate the cytokine-mediated inflammatory response in atherosclerosis.

• Diets high in antioxidant nutrients can protect against diseases of the vasculature by stabilizing vascular endothelial cells.

• Aerobic exercise and weight reduction can decrease postprandial triglyceridemia and thus atherogenic remnant lipoproteins, as well as decrease endothelial cell activation by free fatty acids and lipoprotein remnants.

	Introduction: Endothelial Cell Dysfunction and Atherosclerosis

TOP ABSTRACT Introduction: Endothelial Cell... Hypertriglyceridemia Is an... Atherosclerosis Is a Major... High LPL Activity Is... Endothelial Cell Dysfunction as... Activation of Transcription... Protection by Selected Nutrients... Conclusion REFERENCES

 
Although mortality from coronary heart disease has declined recently, atherosclerosis and related vascular disorders are still the leading cause of death in the United States and other Western countries. The etiology of this disease is multifactorial, with hyperlipidemia, smoking, diabetes mellitus, hypertension and obesity being well established risk factors for the development of atherosclerosis. There are numerous theories for the pathogenesis of atherosclerosis [1], which include theresponse to injury theory [2], modified lipoprotein theory [3], low density lipoprotein (LDL), retention theory [4], and immunological hypothesis for atherosclerosis [5]. The current trend is to consider atherosclerosis as a response of the vascular wall to a variety of initiating agents and multiple pathogenic mechanisms (e.g., hyperlipidemia), contributing to the development of atheromatous plaques. It appears that the major participants in the atherosclerotic disease process include an active vascular endothelium, smooth muscle cells, blood-borne cells such as monocytes and circulating lipoproteins and their remnants [2,6,7]. The result is a multifactorial sequence of events involving endothelial cell injury/dysfunction, uptake of circulating blood monocytes and their differentiation into macrophages, coupled with smooth muscle cell migration and proliferation.

	Hypertriglyceridemia Is an Independent Risk Factor in the Development of Atherosclerosis

TOP ABSTRACT Introduction: Endothelial Cell... Hypertriglyceridemia Is an... Atherosclerosis Is a Major... High LPL Activity Is... Endothelial Cell Dysfunction as... Activation of Transcription... Protection by Selected Nutrients... Conclusion REFERENCES

 
Chronic hypertriglyceridemia or postprandial triglyceridemia, i.e., elevated levels of triglyceride-rich lipoproteins, including chylomicrons, very low density lipoproteins (VLDL) and their remnants, are an independent risk factor in the development and progression of atherosclerosis. Most patients with coronary artery disease have increased postprandial triglyceride levels compared to healthy control subjects [8,9]. Hypertriglyceridemia, particularly when associated with decreased high density lipoproteins (HDL) and abdominal or visceral obesity, is a highly atherogenic phenotype [10]. Furthermore, hypertriglyceridemia is frequently associated with elevated plasma apolipoprotein B concentrations, with states of hyperinsulinemia or insulin resistance, elevated plasma glucose, high blood pressure and small, dense LDL particles, which may further contribute to an increased risk for atherosclerosis [10,11].

The association of hypertriglyceridemia with obesity supports the fact that obesity is a major risk factor for cardiovascular disease. Obesity is pathologically related to several clinical abnormalities such as dyslipidemia that contribute to the development of atherosclerotic plaques and their complications [12]. Obesity has reached epidemic proportions in the United States [13]. Although genetics appear to play a major role in the regulation of body weight [14], there are many environmental factors promoting excess energy intake and discouraging energy expenditure. High energy dense foods contribute to obesity [15], and there is much agreement in the literature that dietary fat plays a key role in the development and treatment of obesity [16]. It appears then that consumption of a high fat diet increases the likelihood of obesity and that the risk of obesity is low in individuals consuming low fat diets [17].

There is evidence that hypertriglyceridemia-induced endothelial cell dysfunction plays a critical role in the pathology of atherosclerosis. Zilversmit [18,19] proposed that the simultaneous release of fatty acids during lipoprotein lipase-mediated triglyceride hydrolysis may cause endothelial cell injury and initiate thrombotic events. Subsequently, much research has been reported supporting fatty acid-mediated endothelial activation and dysfunction as a consequence of hypertriglyceridemia [reviewed in 20]. Furthermore, hypertriglyceridemia can lead to endothelial cell dysfunction associated with increased vascular superoxide anion production and a subsequent decrease in nitric oxide (NO) bioavailability [21]. In addition, it has been reported that leukocyte, and especially monocyte, adhesion to the endothelial surface is stimulated by triglyceride-rich lipoproteins [22,23]. There also is evidence that endothelial cell activation during metabolic states of hypertriglyceridemia and postprandial lipemia is redox sensitive. For example, it has been reported recently that -tocopherol (a potent free radical scavenger and antioxidant nutrient) or N-acetylcysteine (a precursor of glutathione synthesis) can suppress endothelial expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and tissue factor (TF), mediated by remnant-like lipoprotein particles isolated from plasma of hypertriglyceridemic patients [24]. Since most individuals spend 12 to 18 hours daily in a postprandial state, postprandial lipoprotein remnants may thus play a more important role in atherogenesis in hypertriglyceridemic patients than fasting remnant-like lipoprotein particles.

	Atherosclerosis Is a Major Complication of Diabetes

TOP ABSTRACT Introduction: Endothelial Cell... Hypertriglyceridemia Is an... Atherosclerosis Is a Major... High LPL Activity Is... Endothelial Cell Dysfunction as... Activation of Transcription... Protection by Selected Nutrients... Conclusion REFERENCES

 
Hyperinsulinemia, associated with the predominant type 2 diabetes, has been linked to cardiovascular risk factors, i.e., hypertriglyceridemia, low levels of HDL cholesterol, hypertension, hyperglycemia and upper-body obesity [25]. Insulin also stimulates lipid synthesis in arterial tissues, and in particular cholesterol synthesis and LDL binding in both arterial smooth muscle cells and monocyte/macrophages [25]. When correlating postprandial triglyceride levels with carotid intimal-media thickness, it was found that among plasma glucose, postprandial triglycerides and fasting LDL cholesterol levels, postprandial hypertriglyceridemia was most markedly correlated with carotid intimal-media thickness [26]. This suggests that postprandial hypertriglyceridemia, despite normal fasting triglycerides levels, may be an independent risk factor for early atherosclerosis in type 2 diabetes. Specific atherosclerotic risk factors in diabetic patients may be endothelial cell dysfunction [27], increased adherence of mononuclear cells to the endothelium [28], the stimulation of macrophage lipoprotein lipase (LPL) production and overexpression of LPL and TNF- [29].

	High LPL Activity Is Associated with Endothelial Cell Dysfunction and Atherosclerosis

TOP ABSTRACT Introduction: Endothelial Cell... Hypertriglyceridemia Is an... Atherosclerosis Is a Major... High LPL Activity Is... Endothelial Cell Dysfunction as... Activation of Transcription... Protection by Selected Nutrients... Conclusion REFERENCES

 
LPL synthesis, especially LPL synthesis by macrophages, is upregulated in early atherosclerosis, thus implicating the possible involvement of LPL in plaque formation [30]. The proatherosclerotic function of LPL is supported by the findings of Renier et al. [31], who demonstrated in inbred mouse strains that the susceptibility to atherosclerosis is associated with high LPL expression, whereas resistance to atherosclerosis is associated with low LPL levels. LPL is a 60-kD glycoprotein that plays a central role in plasma triglyceride metabolism by hydrolysis of triglyceride-rich chylomicrons and VLDL. LPL is bound to the capillary endothelium by interactions with cell surface proteoglycans and is present in numerous tissues and, especially, in organs with a high demand for free fatty acids, like the heart, skeletal muscle and adipose tissue [32,33]. In atherosclerosis, LPL is overexpressed in vascular lesions and also produced by monocytes, macrophages and smooth muscle cells [34–37]. Thus, high LPL activity in atherosclerotic lesions may play a critical role in the pathology of cardiovascular disease. There is evidence that LPL can increase the retention of LDL and VLDL to the arterial wall [38,39], increase the permeability of the endothelium by formation of lipolysis products [40] and facilitate proteoglycan-mediated monocyte adhesion to the endothelium [41]. Recently, an endothelial-derived lipase with phospholipase activity was cloned from endothelial cells [42]. It was shown in both cultured human umbilical vein and human coronary artery endothelial cells that inflammatory cytokines which are implicated in the etiology of vascular diseases, such as TNF- and IL-1ß, could upregulate endothelial cell-derived LPL mRNA [43]. This may have important implications in understanding mechanisms of vascular diseases because atherosclerosis is now widely considered to be an inflammatory process [44].

In support of hypertriglyceridemia as an important risk factor, high LPL activity and subsequent formation of lipoprotein remnant particles being atherogenic, we have shown that lipoprotein remnants of triglyceride-rich lipoproteins can injure cultured endothelial cells, resulting in decreased endothelial barrier function [45]. This decrease in barrier function appeared to be correlated with the level of free fatty acids (primarily linoleic acid) contained in the lipolytic remnants. Furthermore, we found that lipoprotein remnants derived from human triglyceride-rich lipoproteins produced after a meal rich in polyunsaturated fat were more injurious to cultured vascular endothelial cells than those produced after a meal rich in saturated fat [46]. These data support the hypothesis that postprandial hypertriglyceridemia and the simultaneous release of free fatty acids during LPL-mediated triglyceride hydrolysis in the proximity of the endothelium can cause endothelial cell injury. This may be sufficient to compromise endothelial barrier function, allow for increased uptake of cholesterol-rich lipoprotein remnants into vascular tissues and thus accelerate the pathology of atherosclerosis.

	Endothelial Cell Dysfunction as Affected by Selected Lipids

TOP ABSTRACT Introduction: Endothelial Cell... Hypertriglyceridemia Is an... Atherosclerosis Is a Major... High LPL Activity Is... Endothelial Cell Dysfunction as... Activation of Transcription... Protection by Selected Nutrients... Conclusion REFERENCES

 
There is ample evidence suggesting that serum cholesterol is a predictor of atherosclerosis and that serum cholesterol concentrations can be modified by varying the composition of dietary fat. Less is known, however, about the role of specific fatty acids in atherosclerosis. The role of saturated fatty acids in atherosclerosis has been questioned [47,48]. In fact, data from subjects with varying degrees of coronary atherosclerosis support the hypothesis that high serum polyunsaturated fatty acid levels (e.g., linoleic acid or 18:2n-6), when insufficiently protected by antioxidants (e.g., vitamin E), may indicate a higher risk of atherosclerosis [49]. Research with a population from Israel, a country with one of the highest dietary polyunsaturated/saturated fat ratios in the world, has concluded that diets rich in n-6 fatty acids may contribute to an increased incidence in atherosclerosis, hyperinsulinemia and tumorigenesis [50]. There appears to be a positive correlation between linoleic acid levels in the phospholipid fractions of human coronary arteries and ischemic heart disease [51]. In addition, linoleic acid can increase expression of CD36, a scavenger receptor for oxidized LDL [52], and concentrations of linoleic acid in adipose tissue were positively correlated with the degree of coronary artery disease [53].

There is evidence that selected fatty acids, and especially n-6 unsaturated fatty acids, derived from the hydrolysis of triglyceride-rich lipoproteins, may be atherogenic by causing endothelial injury or dysfunction and subsequent endothelial barrier dysfunction [reviewed in 20]. In support of this hypothesis, we have shown that saturated fatty acids in general had little effect on endothelial barrier function. On the other hand, unsaturated fatty acids, and mostly linoleic acid, can markedly disrupt endothelial barrier function, expressed as an increased transfer of both albumin and LDL across the endothelium [54–56]. Most interestingly, we found that when comparing fatty acid extracts derived from different animal fats and plant oils, the fat-induced disruption of endothelial barrier function was related to the amount of linoleic acid present in the fat source [57]. The impairment of the endothelial barrier function by linoleic acid or linoleic acid hydroperoxide was greatly reduced by preenrichment of cells with vitamin E [58]. In addition to vitamin E, we have shown that endothelial cell exposure to unsaturated fatty acids, and in particular to linoleic acid, can deplete cellular glutathione levels [59]. Similar results were observed after cell exposure to the inflammatory cytokine TNF- [60]. Furthermore, our data strongly support the fact that selected unsaturated fatty acids (e.g., linoleic acid) and inflammatory cytokines may cross-amplify vascular endothelial cell activation, an inflammatory response and atherosclerosis [60,61].

It is now generally accepted that oxidation of LDL plays one of the most critical roles in atherogenesis. LDL can be oxidized in the subendothelial space which lacks many of the antioxidants present in whole blood. It is possible that LDL is oxidized by endothelial cells while passing through the endothelium [62]. In fact, oxidative modifications of LDL were first characterized in vitro using endothelial cell culture model systems [63]. Moreover, other major cell types present in the arterial wall, such as smooth muscle cells and macrophages, are able to oxidize LDL in vitro [64]. However, mechanisms of LDL oxidation still remain controversial.

There is also evidence that in humans dietary oxidized lipids can be absorbed by the small intestine, incorporated into chylomicrons, appear in the bloodstream and thus contribute to the total body pool of oxidized lipids [65]. Including oxidized corn oil in a diet accelerated the development of fatty streaks in cholesterol-fed rabbits [66], suggesting that the consumption of oxidized lipids may be an important risk factor for atherosclerosis. It also has been shown that, compared with normal LDL, mildly oxidized LDL may be atherogenic because it may circulate in plasma for a period sufficiently long to enter, accumulate and be degraded in the arterial intima [67]. Interestingly, when studying lipoproteins from subjects consuming different types of dietary fat, e.g., high in oleic acid or linoleic acid, only the percentage of linoleic acid in LDL correlated strongly with the extent of oxidizability and macrophage degradation of these lipoproteins [68]. We and others also have demonstrated that oleic acid actually can inhibit or down-regulate endothelial cell activation and an inflammatory response [61,69]. This suggests that substitution of monounsaturated (rather than polyunsaturated) fatty acids for saturated fatty acids in the diet might be preferable for the possible prevention of atherosclerosis.

	Activation of Transcription Factors and Cytokine and Adhesion Molecule Expression by Fatty Acids

TOP ABSTRACT Introduction: Endothelial Cell... Hypertriglyceridemia Is an... Atherosclerosis Is a Major... High LPL Activity Is... Endothelial Cell Dysfunction as... Activation of Transcription... Protection by Selected Nutrients... Conclusion REFERENCES

 
Even though numerous risk factors, including hyperlipidemia, smoking and hypertension, seem to contribute to the development of atherosclerosis, to date it has not been possible to link these risk factors into a common pathogenic mechanism. There is evidence, however, that modulations in the level of activity of a select set of endothelial transcription factors (e.g., endothelial nuclear factor-B [NF-B]) may provide a mechanism for linking these seemingly diverse processes with the generation of dysfunctional endothelium and the onset of atherosclerotic lesion formation [70,71]. NF-B plays a central role in regulating the cytokine network, and hence its activation may be a major factor in the pathogenesis of atherosclerosis. NF-B can be activated by a variety of pathogenic or pathogen-elicited stimuli including cytokines, mitogens, bacteria and related products, environmental contaminants, lipids, and the like, with the common denominator apparently being reactive oxygen species. These stimuli cause the phosphorylation of IB and a subsequent proteolytic degradation of this inhibitor subunit, allowing NF-B to translocate into the nucleus, where it binds to recognition sequences in DNA in order to induce gene expression [72]. Many target genes in endothelial cells coding for inflammatory cytokines (e.g., tumor necrosis factor [TNF], interleukin-1 [IL-1], IL-6, IL-8) and adhesion molecules [73] contain NF-B or NF-B-like binding sites in the promoter regions. These adhesion molecules include ICAM-1), VCAM-1 and E-selectin (also known as ELAM-1) [74]. In addition, activated NF-B is found in atherosclerosis lesions [75,76].

All these studies provide evidence that activation of the oxidative stress-sensitive transcription factor NF-B is critical in the expression of inflammatory genes involved in endothelial cell dysfunction and atherosclerosis. We also have demonstrated that linoleic acid-activated NF-B can induce gene expression [77]. For these experiments, endothelial cells were transfected with plasmids encoding chloramphenicol acetyltransferase (CAT; pB/TK5-CAT) or luciferase (pNFB-Luc). Expression of these constructs is controlled by a promoter responsive to NF-B. Results of both CAT and luciferase assays demonstrated that linoleic acid-mediated activation of NF-B is sufficient to induce NF-B-dependent transcription in cultured endothelial cells. CAT and luciferase activities were significantly higher in linoleic acid-treated cells, compared with control cultures [61,77]. Furthermore, we have shown that endothelial cell exposure to linoleic acid can lead to cellular production of inflammatory cytokines, such as IL-6 and IL-8 [78]. These are important findings, because IL-6 appears to be a critical inflammatory cytokine involved in the initiation and progression of atherosclerosis [79–81].

	Protection by Selected Nutrients (e.g., Vitamin E and Zinc) against Lipid/Cytokine-Mediated Endothelial Cell Dysfunction

TOP ABSTRACT Introduction: Endothelial Cell... Hypertriglyceridemia Is an... Atherosclerosis Is a Major... High LPL Activity Is... Endothelial Cell Dysfunction as... Activation of Transcription... Protection by Selected Nutrients... Conclusion REFERENCES

 
After consumption of high-energy diets and during metabolic states of hypertriglyceridemia and postprandial lipemia, vascular endothelial cells experience prolonged exposure to diet-derived lipids, such as free fatty acids, and reactive oxygen metabolites released by blood-borne cells, as well as those generated within the endothelial cells. This provides an environment of increased oxidative stress, which will be detrimental to the cell especially if the overall cellular antioxidant system is inadequate. As mentioned earlier, there is increasing experimental and epidemiological evidence that oxidative modification of plasma lipoproteins, and in particular LDL, plays an important role in the development of atherosclerosis [62,82]. There also is evidence that certain antioxidant nutrients and adequate antioxidant enzyme activities may protect against atherosclerosis by preventing metabolic and physiologic derangements of the vascular endothelium [83]. This may be critical during lipid/cytokine-mediated expression of adhesion molecules and the overall inflammatory process [44,83–86].

Several vitamins and minerals may be involved in metabolic events that protect the vascular endothelium or maintain endothelial integrity. Of particular interest are vitamin E and zinc, because both can function as antioxidants and membrane stabilizers [83,87]. Vitamin E is the only significant lipid-soluble, chain-breaking type of antioxidant present in human blood and all cellular membranes [88–90]. Protective actions of vitamin E could have major implications in preventing vessel wall injury and atherosclerotic lesion formation. Data from humans suggest an inverse correlation between plasma, and especially LDL vitamin E levels, and mortality from ischemic heart disease [91,92]. Part of the protective mechanism of vitamin E is its ability to protect LDL from lipid peroxidation [93–95]. Recent studies also suggest that vitamin E has a potent inhibitory effect on LDL-induced production of adhesion molecules and adhesion of monocytes to endothelial cells via its antioxidant function and apparent direct regulatory effect on adhesion molecule expression [96] and in particular on down-regulation of VCAM-1 [97]. One of the antiinflammatory properties of vitamin E may be its ability to inhibit production of chemokines and inflammatory cytokines [98] and platelet adhesion to activated endothelial cells [99]. Furthermore, data from subjects with varying degrees of coronary atherosclerosis support the hypothesis that high serum polyunsaturated fatty acid levels, when insufficiently protected by antioxidants, e.g., vitamin E, may indicate a higher risk of atherosclerosis [49,53,100].

High-fat diets, and especially diets that contain high levels of polyunsaturated lipids, may be atherogenic by subjecting vascular endothelial cells to oxidative stress. As mentioned above, we have demonstrated that endothelial cells are injured by free fatty acids and in particular by their hydroperoxide derivatives, as evidenced by a decrease in endothelial barrier function [87]. This impairment of the endothelial barrier function was reduced greatly by preenrichment of cells with vitamin E [58]. Antiatherogenic activities of vitamin E in non-endothelial cells also may retard the overall progression of atherosclerosis. For example, vitamin E might act as an antiatherogenic agent by suppressing oxidative modification of LDL [101,102] and thus decrease the cytotoxicity of LDL to endothelial cells [103] and the recruitment of monocytes into the arterial subendothelium by smooth muscle cells [104]. In addition to inhibiting inflammatory mediators, vitamin E also has been shown recently to decrease oxidized LDL-mediated degradation of I-B and apoptosis in cultured human endothelial cells [105]. Vitamin E also can modify protein kinase C activity, decrease platelet aggregation and adhesion and inhibit the interaction of the immune system with the vasculature by preventing the expression of adhesion molecules on the surface of vascular endothelial cells [86].

Mechanisms of the protective function(s) of zinc in the pathogenesis of atherosclerosis, including vascular cell injury/dysfunction and the inflammatory response, are not clear. Epidemiological studies suggest that in some population groups lower serum levels of zinc are associated with coronary artery disease [106]. Furthermore, zinc concentrations were significantly lower in atherosclerotic plaques of abdominal aortas of deceased patients with ischemic heart disease and acute myocardial infarction [107]. There is evidence suggesting that zinc can act as an endogenous protective factor against atherosclerosis by inhibiting the oxidation of LDL by cells or transition metals [108]. In fact, compared with zinc-adequate rats, zinc-deficient rats fed a highly unsaturated fat diet (linseed oil) had increased plasma levels of total lipids and cholesterol and an increased susceptibility of LDL to copper-induced lipid peroxidation [109]. In another study, supplementary antioxidants decreased the osmotic fragility and oxidative damage of erythrocytes in zinc-deficient rats [110]. Most of all, we recently demonstrated that zinc can attenuate oxidative stress-sensitive transcription factors and IL-8 expression in activated endothelial cells [111]. Because of its antioxidant and membrane-stabilizing properties, zinc appears to be crucial for the protection against cell-destabilizing agents such as inflammatory cytokines and polyunsaturated lipids [112].

	Conclusion

TOP ABSTRACT Introduction: Endothelial Cell... Hypertriglyceridemia Is an... Atherosclerosis Is a Major... High LPL Activity Is... Endothelial Cell Dysfunction as... Activation of Transcription... Protection by Selected Nutrients... Conclusion REFERENCES

 
There is compelling evidence that high-energy diets and subsequent chronic hypertriglyceridemia or postprandial lipemia are potent atherogenic risk factors and that nutrition can affect the pathology of atherosclerosis by modulating functional properties of vascular endothelial cells. In particular, the lipid environment of the vascular endothelium may profoundly influence the inflammatory response mediated by cytokines during atherosclerosis. With the discoveries of potential relationships of oxidative stress, activation of oxidative stress-sensitive transcription factors and the etiology of acute and chronic diseases, the issues of types of dietary fat, e.g., saturation/unsaturation, and the pathogenesis of atherosclerosis need to be revisited. Resent data suggest that certain diet-derived unsaturated fatty acids, especially n-6 fatty acids such as linoleic acid, may be proinflammatory and thus atherogenic by disrupting endothelial cell integrity and that nutrients/chemicals with antioxidant properties can protect endothelial cells against lipid-mediated cell injury. Consumption of high-fat and/or high-calorie diets, elevated LPL activity and subsequent hydrolysis of triglyceride-rich lipoproteins may be an important source of high concentrations of cytotoxic fatty acids and postprandial lipoprotein remnants in the proximity of the endothelium. This may be critical during lipid/cytokine-mediated expression of adhesion molecules and the overall inflammatory process. There has been a drive to move our diets to polyunsaturated fatty acids, resulting in massive consumption of the least expensive vegetable oils such as soybean or corn oil, i.e., oils that are rich in linoleic acid. Because of the high intake of linoleic acid in the average American diet, some caution is warranted if its oxidative metabolites predispose individuals to inflammatory diseases. Also, diets high in antioxidant nutrients may protect against diseases of the vasculature by stabilizing vascular endothelial cells. Finally, aerobic exercise and weight reduction can decrease postprandial triglyceridemia and thus atherogenic remnant lipoproteins, as well as decrease endothelial cell activation by free fatty acids and lipoprotein remnants.

Received October 20, 2000. Accepted January 12, 2001.

	REFERENCES

TOP ABSTRACT Introduction: Endothelial Cell... Hypertriglyceridemia Is an... Atherosclerosis Is a Major... High LPL Activity Is... Endothelial Cell Dysfunction as... Activation of Transcription... Protection by Selected Nutrients... Conclusion REFERENCES

 

1. Haudenshild CC: Pathogenesis of atherosclerosis: state of the art. Cardiovasc Drugs Ther 4: 993–1004, 1990.
2. Ross R: The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362: 801–809, 1993.[Medline]
3. Steinberg D, Witztum JL: Lipoproteins and atherosclerosis: current concepts. J Am Med Assoc 264: 3047–3052, 1990.[Abstract]
4. Williams KJ, Tabas I: The response-to-retention hypothesis of early atherosclerosis. Arterioscler Thromb Vasc Biol 15: 551–561, 1995.[Free Full Text]
5. Wick G, Romen M, Amberger A, Metzler B, Mayr M, Falkensammer G, Xu Q: Atherosclerosis, autoimmunity, and vascular-associated lymphoid tissue. FASEB J 11: 1199–1207, 1997.[Medline]
6. Munro JM, Cotran RS: The pathogenesis of atherosclerosis: atherogenesis and inflammation. Lab Invest 58: 249–261, 1988.[Medline]
7. Simionescu M, Simionescu N: Proatherosclerotic events: pathobiochemical changes occurring in the arterial wall before monocyte migration. FASEB J 7: 1359–1366, 1993.[Abstract]
8. Cohn JS: Postprandial lipemia: emerging evidence for atherogenicity of remnant lipoproteins. Can J Cardiol 14(Suppl B): 18B–27B, 1998.
9. Boquist S, Ruotolo G, Tang R, Bjorkegren J, Bond MG, de Faire U, Karpe F, Hamsten A: Alimentary lipemia, postprandial triglyceride-rich lipoproteins, and common carotid intima-media thickness in healthy, middle-aged men. Circulation 100: 723–728, 1999.[Abstract/Free Full Text]
10. Lamarche B, Lewis GF: Atherosclerosis prevention for the next decade: risk assessment beyond low density lipoprotein cholesterol. Can J Cardiol 14: 841–851, 1998.[Medline]
11. Grundy SM: Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. Am J Cardiol 83: 25F–29F, 1999.[Medline]
12. Abate N: Obesity and cardiovascular disease. Pathogenetic role of the metabolic syndrome and therapeutic implications. J Diabetes Complications 14: 154–174, 2000.[Medline]
13. Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL: Overweight and obesity in the United States: prevalence and trends, 1960–1994. Int J Obes Relat Metab Disord 22: 39–47, 1998.[Medline]
14. Bouchard C, Tremblay A: Genetic influences on the response of body fat and fat distribution to positive and negative energy balances in human identical twins. J Nutr 127: 943S–947S, 1997.
15. Rolls BJ: The role of energy density in the overconsumption of fat. J Nutr 130: 268S–271S, 2000.
16. Bray GA, Popkin BM: Dietary fat intake does affect obesity! Am J Clin Nutr 68: 1157–1173, 1998.[Abstract]
17. Hill JO, Melanson EL, Wyatt HT: Dietary fat intake and regulation of energy balance: implications for obesity. J Nutr 130: 284S–288S, 2000.
18. Zilversmit DB: A proposal linking atherogenesis to the interaction of endothelial lipoprotein lipase with triglyceride-rich lipoproteins. Circ Res 33: 633–638, 1973.[Free Full Text]
19. Zilversmit DB: Atherogenic nature of triglycerides, postprandial lipidemia, and triglyceride-rich remnant lipoproteins. Clin Chem 41: 153–158, 1995.[Abstract/Free Full Text]
20. Hennig B, Toborek M, McClain CJ, Diana JN: Nutritional implications in vascular endothelial cell metabolism. J Am Coll Nutr 15: 345–358, 1996.[Abstract]
21. Kusterer K, Pohl T, Fortmeyer HP, Marz W, Scharnagl H, Oldenburg A, Angermuller S, Fleming I, Usadel KH, Busse R: Chronic selective hypertriglyceridemia impairs endothelium-dependent vasodilatation in rats. Cardiovasc Res J 42: 783–793, 1999.
22. de Gruijter M, Hoogerbrugge N, van Rijn MA, Koster JF, Sluiter W, Jongkind JF: Patients with combined hypercholesterolemia-hypertriglyceridemia show an increased monocyte-endothelial cell adhesion in vitro: triglyceride level as a major determinant. Metabolism 40: 1119–1121, 1991.[Medline]
23. Dart AM, Chin-Dusting JP: Lipids and the endothelium. Cardiovasc Res 43: 308–322, 1999.[Abstract/Free Full Text]
24. Doi H, Kugiyama K, Oka H, Sugiyama S, Ogata N, Koide SI, Nakamura SI, Yasue H: Remnant lipoproteins induce proatherothrombogenic molecules in endothelial cells through a redox-sensitive mechanism. Circulation 102: 670–676, 2000.[Abstract/Free Full Text]
25. Stout RW: Insulin and atheroma. 20-yr perspective. Diabetes Care 13: 631–654, 1990.[Abstract]
26. Teno S, Uto Y, Nagashima H, Endoh Y, Iwamoto Y, Omori Y, Takizawa T: Association of postprandial hypertriglyceridemia and carotid intima-media thickness in patients with type 2 diabetes. Diabetes Care 23: 1401–1406, 2000.[Abstract/Free Full Text]
27. Hogikyan RV, Galecki AT, Pitt B, Halter JB, Greene DA, Supiano MA: Specific impairment of endothelium-dependent vasodilation in subjects with type 2 diabetes independent of obesity. J Clin Endocrinol Metab 83: 1946–1952, 1998.[Abstract/Free Full Text]
28. Carantoni M, Abbasi F, Chu L, Chen YD, Reaven GM, Tsao PS, Varasteh B, Cooke JP: Adherence of mononuclear cells to endothelium in vitro is increased in patients with NIDDM. Diabetes Care 20: 1462–1465, 1997.[Abstract]
29. Sartippour MR, Renier G: Upregulation of macrophage lipoprotein lipase in patients with type 2 diabetes: role of peripheral factors. Diabetes 49: 597–602, 2000.[Abstract]
30. Van Eck M, Zimmermann R, Groot PH, Zechner R, Van Berkel TJ: Role of macrophage-derived lipoprotein lipase in lipoprotein metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol 20: E53–62, 2000.
31. Renier G, Skamene E, DeSanctis JB, Radzioch D: High macrophage lipoprotein lipase expression and secretion are associated in inbred murine strains with susceptibility to atherosclerosis. Arterioscler Thromb 13: 190–196, 1993.[Abstract/Free Full Text]
32. Zechner R: The tissue-specific expression of lipoprotein lipase: implications for energy and lipoprotein metabolism. Curr Opin Lipidol 8: 77–88, 1997.[Medline]
33. Semenkovich CF, Chen SH, Wims M, Luo CC, Li WH, Chan L: Lipoprotein lipase and hepatic lipase mRNA tissue specific expression, developmental regulation, and evolution. J Lipid Res 30: 423–431, 1989.[Abstract]
34. Khoo JC, Mahoney EM, Witztum JL: Secretion of lipoprotein lipase by macrophages in culture. J Biol Chem 256: 7105–7108, 1981.[Abstract/Free Full Text]
35. Ylä-Herttuala S, Lipton BA, Rosenfeld ME, Goldberg IJ, Steinberg D, Witztum JL: Macrophages and smooth muscle cells express lipoprotein lipase in human and rabbit atherosclerotic lesions. Proc Natl Acad Sci USA. 88: 10143–10147, 1991.[Abstract/Free Full Text]
36. O’Brien KD, Gordon D, Deeb S, Ferguson M, Chait A: Lipoprotein lipase is synthesized by macrophage-derived foam cells in human coronary atherosclerotic plaques. J Clin Invest 89: 1544–1550, 1992.
37. Sofer O, Fainaru M, Schafer Z, Goldman R: Regulation of lipoprotein lipase secretion in murine macrophages during foam cell formation in vitro. Effect of triglyceride-rich lipoproteins. Arterioscler Thromb 12: 1458–1466, 1992.[Abstract/Free Full Text]
38. Saxena U, Klein MG, Vanni TM, Goldberg IJ: Lipoprotein lipase increases low density lipoprotein retention by subendothelial cell matrix. J Clin Invest 89: 373–380, 1992.
39. Edwards IJ, Goldberg IJ, Parks JS, Xu H, Wagner WD: Lipoprotein lipase enhances the interaction of low density lipoproteins with artery-derived extracellular matrix proteoglycans. J Lipid Res 34: 1155–1163, 1993.[Abstract]
40. Rutledge JC, Woo MM, Rezai AA, Curtiss LK, Goldberg IJ: Lipoprotein lipase increases lipoprotein binding to the artery wall and increases endothelial layer permeability by formation of lipolysis products. Circ Res 80: 819–828, 1997.[Abstract/Free Full Text]
41. Mamputu JC, Desfaits AC, Renier G: Lipoprotein lipase enhances human monocyte adhesion to aortic endothelial cells. J Lipid Res 38: 1722–1729, 1997.[Abstract]
42. Hirata K, Dichek HL, Cioffi JA, Choi SY, Leeper NJ, Quintana L, Kronmal GS, Cooper AD, Quertermous T: Cloning of a unique lipase from endothelial cells extends the lipase gene family. J Biol Chem 274: 14170–14175, 1999.[Abstract/Free Full Text]
43. Hirata K, Ishida T, Matsushita H, Tsao PS, Quertermous T: Regulated expression of endothelial cell-derived lipase. Biochem Biophys Res Commun 272: 90–93, 2000.[Medline]
44. Ross R: Atherosclerosis—an inflammatory disease. N Engl J Med 340: 115–126, 1999.[Free Full Text]
45. Hennig B, Chung BH, Watkins BA, Alvarado A: Disruption of endothelial barrier function by lipolytic remnants of triglyceride-rich lipoproteins. Atherosclerosis 95: 235–247, 1992.[Medline]
46. Chung BH, Hennig B, Cho BH, Darnell BE: Effect of the fat composition of a single meal on the composition and cytotoxic potencies of lipolytically-releasable free fatty acids in postprandial plasma. Atherosclerosis 141: 321–332, 1998.[Medline]
47. Mensink RP: Effects of the individual saturated fatty acids on serum lipids and lipoprotein concentrations. Am J Clin Nutr 57: 711S–714S, 1993.[Abstract/Free Full Text]
48. Hegsted DM, McGandy RB, Myers ML, Stare FJ: Quantitative effects of dietary fat on serum cholesterol in man. Am J Clin Nutr 17: 281–295, 1965.[Medline]
49. Kok FJ, van Poppel G, Melse J, Verheul E, Schouten EG, Kruyssen DHCM, Hofman A: Do antioxidants and polyunsaturated fatty acids have a combined association with coronary atherosclerosis? Atherosclerosis 31: 85–90, 1991.
50. Yam D, Eliraz A, Berry EM: Diet and disease, the Israeli paradox: possible dangers of a high omega-6 polyunsaturated fatty acid diet. Isr J Med Sci 32: 1134–1143, 1996.[Medline]
51. Loustarinen R, Boberg M, Saldeen T: Fatty acid composition in total phospholipids of human coronary arteries in sudden cardiac death. Atherosclerosis 99: 187–193, 1993.[Medline]
52. Pietsch A, Weber C, Goretzki M, Weber PC, Lorenz RL: N-3 but not N-6 fatty acids reduce the expression of the combined adhesion and scavenger receptor CD 36 in human monocyte cells. Cell Biochem Funct 13: 211–216, 1995.[Medline]
53. Hodgson JM, Wahlquist ML, Boxall JA, Balazs ND: Can linoleic acid contribute to coronary artery disease? Am J Clin Nutr 58: 228–234, 1993.[Abstract/Free Full Text]
54. Hennig B, Shasby DM, Fulton AB, Spector AA: Exposure to free fatty acid increases the transfer of albumin across cultured endothelial monolayers. Arteriosclerosis 4: 489–497, 1984.[Abstract/Free Full Text]
55. Hennig B, Shasby DM, Spector AA: Exposure to fatty acid increases human low density lipoprotein transfer across cultured endothelial monolayers. Circ Res 57: 776–780, 1985.[Abstract/Free Full Text]
56. Hennig B, Alvarado A, Ramasamy S, Boissonneault GA, Decker E, Means WJ: Fatty acid induced disruption of endothelial barrier function in culture. Biochem Arch 6: 409–417, 1990.
57. Hennig B, Ramasamy S, Alvarado A, Shantha NC, Boissonneault GA, Decker EA, Watkins BA: Selective disruption of endothelial barrier function in culture by pure fatty acids and fatty acids derived from animal and plant fats. J Nutr 123: 1208–1216, 1993.
58. Hennig B, Enoch C, Chow C K: Protection by vitamin E against endothelial cell injury by linoleic acid hydroperoxides. Nutr Res 7: 1253–1260, 1987.
59. Toborek M, Hennig B: Fatty acid-mediated effects on the glutathione redox cycle in cultured endothelial cells. Am J Clin Nutr 59: 60–65, 1994.[Abstract/Free Full Text]
60. Toborek M, Barger SW, Mattson MP, Barve S, McClain CJ, Hennig B: Linoleic acid and TNF- cross-amplify oxidative injury and dysfunction of endothelial cells. J Lipid Res 37: 123–135, 1996.[Abstract]
61. Hennig B, Meerarani P, Ramadass P, Watkins BA, Toborek M: Fatty acid-mediated activation of vascular endothelial cells. Metabolism 49: 1006–1013, 2000.[Medline]
62. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL: Beyond cholesterol: modification of low density lipoprotein that increase its atherogenicity. N Engl J Med 320: 915–924, 1989.[Medline]
63. Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D: Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci USA 81: 3883–3887, 1984.[Abstract/Free Full Text]
64. Witztum JL: Role of oxidised low density lipoprotein in atherogenesis. Br Heart J 69: S12–S18, 1993.
65. Staprans I, Rapp JH, Pan XM, Kim KY, Feingold KR: Oxidized lipids in the diet are a source of oxidized lipid in chylomicrons of human serum. Arterioscler Thromb Vasc Biol 14: 1900–1905, 1994.[Abstract/Free Full Text]
66. Staprans I, Rapp JH, Pan XM, Hardman DA, Feingold KR: Oxidized lipids in the diet accelerate the development of fatty streaks in cholesterol-fed rabbits. Arterioscler Thromb Vasc Biol 16: 533–538, 1996.[Abstract/Free Full Text]
67. Juul K, Nielsen LB, Munkholm K, Stender S, Nordestgaard BG: Oxidation of plasma low-density lipoprotein accelerates its accumulation and degradation in the arterial wall in vivo. Circulation 94: 1698–1704, 1996.[Abstract/Free Full Text]
68. Reaven P, Parthasarathy S, Grasse BJ, Miller E, Steinberg D, Witztum JL: Effects of oleate-rich and linoleate-rich diets on the susceptibility of low density lipoprotein to oxidative modification in mildly hypercholesterolemic subjects. J Clin Invest 91: 668–676, 1993.
69. Carluccio MA, Massaro M, Bonfrate C, Siculella L, Maffia M, Nicolardi G, Distante A, Storelli C, De Caterina R: Oleic acid inhibits endothelial activation: A direct vascular antiatherogenic mechanism of a nutritional component in the mediterranean diet. Arterioscler Thromb Vasc Biol 19: 220–228, 1999.[Abstract/Free Full Text]
70. Collins T: Endothelial nuclear factor-B and the initiation of the atherosclerotic lesion. Lab Invest 68: 499–508, 1993.[Medline]
71. Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA, Watson AD, and Lusis AJ: Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation 91: 2488–2496, 1995.[Abstract/Free Full Text]
72. Traenckner EB, Pahl HL, Henkel T, Schmidt KN, Wilk S, Baeuerle PA: Phosphorylation of human I kappa B-alpha on serines 32 and 36 controls I kappa B-alpha proteolysis and NF-kappa B activation in response to diverse stimuli. EMBO J 14: 2876–2883, 1995.[Medline]
73. Baeuerle PA, Henkel T: Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 12: 141–179, 1994.[Medline]
74. Osborn L, Hession C, Tizard R, Vassallo C, Luhowskyj S, Chi-Rosso G, Lobb R: Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell 59: 1203–1211, 1989.[Medline]
75. Brand K, Page S, Rogler G, Bartsch A, Brandl R, Knuechel R, Page M, Kaltschmidt C, Baeuerle PA, Neumeier D: Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J Clin Invest 97: 1715–1722, 1996.[Medline]
76. Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T, Cybulsky MI: The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Proc Natl Acad Sci USA 97: 9052–9057, 2000.[Abstract/Free Full Text]
77. Hennig B, Toborek M, Joshi-Barve S, Barger SW, Barve S, Mattson MP, McClain CJ: Linoleic acid activates nuclear transcription factor-kappa B (NF-kappa B) and induces NF-kappa B-dependent transcription in cultured endothelial cells. Am J Clin Nutr 63: 322–328, 1996.[Abstract/Free Full Text]
78. Young VM, Toborek M, Yang F, McClain CJ, Hennig B: Effect of linoleic acid on endothelial cell inflammatory mediators. Metabolism 47: 566–572, 1998.[Medline]
79. Seino Y, Ikeda U, Ikeda M, Yamamoto K, Misawa Y, Hasegawa T, Kano S, Shimada K: Interleukin-6 gene transcripts are expressed in human atherosclerotic lesions. Cytokine 6: 87–91, 1994.[Medline]
80. Rus HG, Vlaicu R, Niculescu F: Interleukin-6 and interleukin-8 protein and gene expression in human arterial atherosclerotic wall. Atherosclerosis 127: 263–271, 1996.[Medline]
81. Yudkin JS, Kumari M, Humphries SE, Mohamed-Ali V: Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 148: 209–214, 2000.[Medline]
82. Esterbauer H, Gebicki J, Puhl H, Jürgens G: The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Rad Biol Med 13: 341–390, 1992.[Medline]
83. Hennig B, Diana J N, Toborek M, McClain C J: Influence of nutrients and cytokines on endothelial cell metabolism. J Am Coll Nutr 13: 224–231, 1994.[Abstract]
84. Faruqi R, de la Motte C, DiCorleto PE: -Tocopherol inhibits agonist-induced monocytic cell adhesion to cultured human endothelial cells. J Clin Invest 94: 592–600, 1994.
85. Grimble RF: Nutritional antioxidants and the modulation of inflammation: theory and practice. New Horiz 2: 175–185, 1994.[Medline]
86. Offermann MK, Medford RM: Antioxidants and atherosclerosis: a molecular perspective. Heart Dis Stroke 3: 52–57, 1994.[Medline]
87. Hennig B, Alvarado A: Nutrition and endothelial cell integrity: Implications in atherosclerosis. Prog Food Nutr Sci 17: 119–157, 1993.[Medline]
88. Machlin LJ, Bendich A: Free radical tissue damage: protective role of antioxidant nutrients. FASEB J 1: 441–445, 1987.[Abstract]
89. Niki E: Antioxidants in relation to lipid peroxidation. Chem Phys Lipids 44: 227–253, 1987.[Medline]
90. DiMascio P, Murphy M E, Sies H: Antioxidant defense systems: the role of carotenoids, tocopherols, and thiols. Am J Clin Nutr 53: 194S–200S, 1991.[Abstract/Free Full Text]
91. Gey KF, Puska P, Jordan P, Moser UK: Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Am J Clin Nutr 53: 326S–334S, 1991.[Abstract/Free Full Text]
92. Regenström J, Nilsson J, Moldeus P, Ström K, Bavenholm P, Tornvall P, Hamsten A: Inverse relation between the concentration of low-density-lipoprotein vitamin E and severity of coronary artery disease. Am J Clin Nutr 63: 377–385, 1996.[Abstract/Free Full Text]
93. Jialal I, Fuller CJ, Huet BA: The effect of -tocopherol supplementation of LDL oxidation. Arterioscler Thromb Vasc Biol 15: 190–198, 1995.[Abstract/Free Full Text]
94. Princen HMG, van Duyvenvoorde W, Buytenhek R, van der Laarse A, van Poppel G, Gevers-Leuven JA, van Hinsbergh VWM: Supplementation with low doses of vitamin E protects LDL from lipid peroxidation in men and women. Arterioscler Thromb Vasc Biol 15: 325–333, 1995.[Abstract/Free Full Text]
95. Devaraj S, Adams-Huet B, Fuller CJ, Jialal I: Dose-response comparison of RRR--tocopherol and all-racemic -tocopherol on LDL oxidation. Arterioscler Thromb Vasc Biol 17: 2273–2279, 1997.[Abstract/Free Full Text]
96. Matin A, Foxall T, Blumberg JB, Meydani M: Vitamin E inhibits low-density lipoprotein-induced adhesion of monocytes to human aortic endothelial cells in vitro. Arterioscler Thromb Vasc Biol 17: 429–436, 1997.[Abstract/Free Full Text]
97. Zapolska-Downar D, Zapolski-Downar A, Markiewski M, Ciechanowicz A, Kaczmarczyk M, Naruszewicz M: Selective inhibition by alpha-tocopherol of vascular cell adhesion molecule-1 expression in human vascular endothelial cells. Biochem Biophys Res Commun 274: 609–615, 2000.[Medline]
98. Wu D, Koga T, Martin KR, Meydani M: Effect of vitamin E on human aortic endothelial cell production of chemokines and adhesion to monocytes. Atherosclerosis 147: 297–307, 1999.[Medline]
99. Szuwart T, Brzoska T, Luger TA, Filler T, Peuker E, Dierichs R: Vitamin E reduces platelet adhesion to human endothelial cells in vitro. Am J Hematol 65: 1–4, 2000.[Medline]
100. Manson JE, Gaziano JM, Jonas MA, Hennekens CH: Antioxidants and cardiovascular disease: a review. J Am Coll Nutr 12: 426–432, 1993.[Abstract]
101. Esterbauer H, Dieber-Rotheneder M, Striegl G, Waeg G: Role of vitamin E in preventing the oxidation of low-density lipoprotein. Am J Clin Nutr 53: 314S–321S, 1991.[Abstract/Free Full Text]
102. Dieber-Rotheneder M, Puhl H, Waeg G, Striegl G, Esterbauer H: Effect of oral supplementation with D--tocopherol on the vitamin E content of human low density lipoproteins and resistance to oxidation. J Lipid Res 32: 1325–1332, 1992.[Abstract]
103. Belcher JD, Balla J, Balla G, Jacobs Jr DR, Gross M, Jaboc HS, Vercellotti GM: Vitamin E, LDL, and endothelium. Brief oral vitamin supplementation prevents oxidized LDL-mediated vascular injury in vitro. Arterioscler Thromb 13: 1779–1789, 1993.[Abstract/Free Full Text]
104. Janero DR: Therapeutic potential of vitamin E in the pathogenesis of spontaneous atherosclerosis. Free Rad Biol Med 11: 129–144, 1991.[Medline]
105. Li D, Saldeen T, Mehta JL: Effects of alpha-tocopherol on ox-LDL-mediated degradation of IkappaB and apoptosis in cultured human coronary artery endothelial cells. J Cardiovasc Pharmacol 36: 297–301, 2000.[Medline]
106. Singh RB, Gupta UC, Mittal N, Niaz MA, Ghosh S, Rastogi V: Epidemiologic study of trace elements and magnesium on risk of coronary artery disease in rural and urban Indian populations. J Am Coll Nutr 16: 62–67, 1997.[Abstract]
107. Vlad M, Caseanu E, Uza G, Petrescu M: Concentration of copper, zinc, chromium, iron and nickel in the abdominal aorta of patients deceased with coronary heart disease. J Trace Elem Electrolytes Health Dis 8: 111–114, 1994.[Medline]
108. Wilkins GM, Leake DS: The oxidation of low density lipoprotein by cells or iron is inhibited by zinc. FEBS Letters 341: 259–262, 1994.[Medline]
109. Eder K, Kirchgessner M: Concentrations of lipids in plasma and lipoproteins and oxidative susceptibility of low-density lipoproteins in zinc-deficient rats fed linseed oil or olive oil. J Nutr Biochem 8: 461–468, 1997.
110. Kraus A, Roth HP, Kirchgessner M: Supplementation with vitamin C, vitamin E or ß-carotene influences osmotic fragility and oxidative damage of erythrocytes of zinc-deficient rats. J Nutr 127: 1290–1296, 1997.[Abstract/Free Full Text]
111. Connell P, Young VM, Toborek M, Cohen DA, Barve S, McClain CJ, Hennig B: Zinc attenuates tumor necrosis factor-mediated activation of transcription factors in endothelial cells. J Am Coll Nutr 16: 411–417, 1997.[Abstract]
112. Hennig B, Toborek M, McClain CJ: Antiatherogenic properties of zinc: implications in endothelial cell metabolism. Nutrition 12: 711–717, 1996.[Medline]

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