Influence of trans fatty acids on endothelial cell dysfunction and possible therapeutic effects of physical activity on endothelial tissue for prevention or regression of atherosclerosis

Masi, Laureane Nunes; Silva, Érica Paula Portioli

doi:10.1590/S1677-54492009000200012

Abstracts

The endothelium actively participates in the regulation of vascular tone through the synthesis and release of vasoactive mediators. Inflammation and cardiovascular risk factors affect vascular homeostasis, causing endothelial dysfunction and atheromatous plaque formation. Increased free fatty acid concentrations may result in vascular lipotoxicity, endothelium dysfunction and, ultimately, atherosclerosis. A lipid-rich diet including trans fatty acids has a positive correlation with the progression of cardiovascular diseases. Lifestyle changes, such as eating a well-balanced diet and participating in regular physical activity, have been proposed to prevent cardiovascular diseases and improve rehabilitation. In this review, we discuss the beneficial effects of regular exercise on important aspects of endothelial dysfunction caused by trans fatty acids, including recent and/or yet-to-be-described evidence. The discussion also comprehends the mechanisms involved in endothelial cell dysfunction due to increased trans fatty acid concentrations.

Trans fatty acids; vascular endothelium; hysical activity

O endotélio atua ativamente na regulação do tônus vascular, sintetizando e liberando substâncias vasoativas. A inflamação e os fatores de risco cardiovasculares alteram a homeostase vascular, levando à disfunção endotelial e possível formação de placas de ateroma. O aumento das concentrações plasmáticas de ácidos graxos livres pode causar lipotoxicidade vascular, disfunção do endotélio e, finalmente, aterosclerose. Dieta rica em lipídeos contendo ácidos graxos trans tem correlação positiva com a progressão de doenças cardiovasculares. Mudanças no estilo de vida, na adoção de dieta balanceada e atividade física são estratégias para a prevenção de doenças cardiovasculares e a reabilitação de pacientes. Nesta revisão, discutimos a influência benéfica do exercício físico em aspectos importantes da disfunção endotelial causados pelos ácidos graxos trans, incluindo evidências recentes e/ou ainda não exploradas. Discutimos também quais seriam os mecanismos envolvidos no comprometimento funcional da célula endotelial frente ao aumento de ácidos graxos trans na circulação.

Ácido graxo trans; endotélio vascular; exercício físico

REVIEW ARTICLE

Influence of trans fatty acids on endothelial cell dysfunction and possible therapeutic effects of physical activity on endothelial tissue for prevention or regression of atherosclerosis

Laureane Nunes Masi; Érica Paula Portioli Silva

Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, (USP), São Paulo, SP, Brazil

Correspondence

ABSTRACT

The endothelium actively participates in the regulation of vascular tone through the synthesis and release of vasoactive mediators. Inflammation and cardiovascular risk factors affect vascular homeostasis, causing endothelial dysfunction and atheromatous plaque formation. Increased free fatty acid concentrations may result in vascular lipotoxicity, endothelium dysfunction and, ultimately, atherosclerosis. A lipid-rich diet including trans fatty acids has a positive correlation with the progression of cardiovascular diseases. Lifestyle changes, such as eating a well-balanced diet and participating in regular physical activity, have been proposed to prevent cardiovascular diseases and improve rehabilitation. In this review, we discuss the beneficial effects of regular exercise on important aspects of endothelial dysfunction caused by trans fatty acids, including recent and/or yet-to-be-described evidence. The discussion also comprehends the mechanisms involved in endothelial cell dysfunction due to increased trans fatty acid concentrations.

Keywords:Trans fatty acids, vascular endothelium, physical activity.

Introduction

The endothelium is not an inert, single-cell tissue line covering the internal surface of blood vessels, but actively participates in the regulation of vascular tone and structure.¹ The vascular endothelium is sensitive to humoral and hormonal factors, synthesizing and releasing vasoactive substances. Vascular homeostasis is maintained by a balance between endothelium-derived relaxing and contracting factors. When this balance is interrupted, which occurs during inflammatory response induced by cardiovascular risk factors, the vasculature becomes susceptible to atheroma formation.² Endothelial dysfunction refers to impaired endothelium-dependent vasodilation or decreased nitric oxide release, as well to endothelial nitric oxide synthase activity or expression inhibition. The most common conditions predisposing individuals to atherosclerosis, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with endothelial dysfunction, inducing a proinflammatory and prothrombotic phenotype of the endothelium.¹ Increased plasma free fatty acid concentrations cause a reduction in endothelial nitric oxide synthase activity and a consequent decrease in nitric oxide, leading to an increase in endothelial superoxide anion production.³ Therefore, increased plasma lipid levels may be a factor for vascular lipotoxicity, endothelium dysfunction, and atherosclerosis.⁴

Currently, there is a growing interest about the effects of a diet rich in trans fatty acids and the progression of cardiovascular diseases. Epidemiological studies have demonstrated that an increase of 2% in the intake of trans fatty acids is associated with a higher risk for coronary heart disease.⁵ The association between the intake of trans fatty acids and cardiovascular disease risk is more evident than that between the intake of saturated fatty acids and cardiovascular disease risk. Although trans fatty acids have been removed from most manufactured foods, it is still unknown which mechanisms affect the integrity of vascular endothelial cells.

Endothelial dysfunction and trans fatty acids: foam cell formation?

In response to pathological stimuli, such as hypertension, diabetes and hypercholesterolemia, endothelial function changes, leading to endothelial dysfunction.^6,7 Endothelial dysfunction is characterized by chronic endothelial activation, which includes increased proinflammatory cytokine production⁸ and decreased nitric oxide-dependent vasodilation capacity.⁹ Furthermore, there are alterations in the production of prostaglandin and endothelium-derived hyperpolarizing factors, as well as an increased endothelial superoxide anion production (leading to nitric oxide inactivation) and proinflammatory and prothrombotic activation of endothelium.¹⁰ Normal fatty acid homeostasis involves the balance between the formation or release of fatty acids by the adipose tissue and their use by tissues such as muscles and the liver. Cells accumulate extra fatty acids as triglycerides when the offer exceeds the amount required for anabolism and catabolism. Adipose tissue can store large amounts of fatty acids as triglycerides, whereas other tissues have a limited capacity for the storage of lipids. Lipotoxicity occurs when excessive amounts of lipids accumulate in non-adipose tissues, resulting in cell dysfunction and apoptosis.¹¹

After the success of hydrogenated vegetable oils in 1897, the intake of unsaturated trans fatty acid isomers has increased significantly in human diets.¹² Such isomers are present in manufactured foods, such as cookies, salted snacks and margarine. Trans fatty acids comprise a class of unsaturated fatty acids that contain in their chain a double bond in the trans configuration. In general, these fatty acids naturally occur in the fat of ruminants, which is formed by the enzymatic hydrogenation of several polyunsaturated fatty acids (such as linoleic acid) in the rumen. These fatty acids are also formed during industrial hydrogenation of vegetable oils. Although ruminant fat and partially hydrogenated vegetable oils contain the same trans fatty acid isomer, the isomeric profile is clearly different. In ruminant fat, trans-11 18:1 (trans-11 18:1; vaccenic acid) represents 60-80% of the total,¹³ and partially hydrogenated vegetable oils essentially have trans-9 18:1 (elaidic acid).¹⁴ The effects of trans fatty acid intake on human health have been studied,¹⁵ and it is known that these effects are correlated with a variety of dysfunctions, especially cardiovascular diseases. Several epidemiological studies have correlated high intakes of trans fatty acids with increased morbidity and mortality caused by cardiovascular diseases.¹⁶ In a study conducted with 730 women, higher intake of trans fatty acids was associated with increased expression of intercellular cell adhesion molecules 1 (ICAM-1) and vascular cell adhesion molecules 1 (VCAM-1) and increased plasma concentration of E-selectin, which are markers of endothelial dysfunction.¹⁷

In comparison with saturated or cis-unsaturated fat, trans fatty acids increase low-density lipoprotein (LDL) cholesterol, reduce high-density lipoprotein (HDL) cholesterol, and increase total cholesterol content. The reduced proportion of HDL cholesterol is a risk factor for the development of cardiovascular diseases.¹⁸ The relation between the intake oftrans fatty acids and the incidence of cardiovascular disease reported in prospective studies is greater than one would predict based on changes in serum lipid content,^19-21 suggesting that trans fatty acids may also affect other cardiovascular disease risk factors.

The basic mechanism of the effects of trans fatty acids on inflammatory processes and endothelial function is yet to be established. However, the effects of other fatty acids are known in the intracellular pathway, as well as the responses through incorporation of fatty acids into cell-membrane phospholipids, altering the function of specific receptors ²² and through direct ligand binding and modulation of nuclear receptors that regulate the transcription of genes.²³ The effects of trans fatty acids are mediated through the same pathways. For exemple, trans fatty acids are incorporated into endothelial cell membranes, monocytes/macrophages and adipocytes, affecting inflammation-related signaling pathways.²⁴ The intake of trans fatty acids changes the inflammatory response of cultured mononuclear cells.

Trans fatty acids activate the inflammatory system, increasing the content of interleukin-6 (IL-6), tumor necrosis factor-Î± (TNF-Î±), tumor necrosis factor receptors, and monocyte chemoattractant protein-1 (MCP-1).²⁵ They also promote vascular dysfunction by a reduction in brachial artery blood flow.²⁶

Over 2 decades ago, Kinsella et al.²⁷ and more recently Kummerow et al.²⁸ demonstrated that trans fatty acids influence prostaglandin balance, which causes thrombogenesis and inhibits the conversion of linoleic acid into arachidonic acid, modifying the metabolism of fatty acids and causing changes in phospholipid fatty acid composition in the aorta of male Wistar rats.

The modifying effect on body mass index observed in the relation between the intake of trans fatty acids and circulating IL-6 and C-reactive protein levels suggests that proinflammatory effects may be partially mediated by the responses of adipose tissue.²⁹ Similar to other fatty acids,³⁰trans fatty acids may bind to nuclear receptors of adipocytes and other tissues, including peroxisome proliferator-activated receptor (PPAR-gamma), liver X receptor, and sterol regulatory element binding protein-1, regulating genes that affect cardiovascular risk factors through lipid- and non-lipid-related actions. In studies conducted in animal models, the intake of trans fatty acids altered gene expression in adipocytes such as PPAR-gamma, resistin and lipoprotein lipase.³¹Trans fatty acids also influence the metabolism of other fatty acids in human adipocytes.³²

These studies demonstrated that trans fatty acids are associated with the development of cardiovascular diseases, probably due to the induction of proinflammatory vascular response.³³ However, the way and extent to which trans fatty acids affect the vasculature remain unknown.

Effects of physical activity on endothelial dysfunction

The association of coronary risk factors and cardiovascular disease with endothelial dysfunction indicates that an intervention to reduce risk factors and improve endothelial function should reduce ischemic heart disease and unstable coronary syndromes. Therapeutic interventions include the use of statin, estrogen, vitamins E and C, angiotensin-converting enzyme inhibitors, and physical activity.

Physical activity reduces cardiovascular risks. Although aerobic training and endothelium-dependent vasodilation show a positive correlation, only a few studies have been carried out in this area. Furthermore, the studies have used different types of physical exercise and mixed populations (normal, hypertensive, coronary patients). Thus, each situation needs to be considered individually, and the results cannot be generalized. Hambrecht et al.³⁴ demonstrated that 4 weeks of vigorous exercise training improves endothelial dysfunction in patients with symptoms of cardiovascular disease. Coronary vasoconstriction in response to infusion of acetylcholine was attenuated after a 4-week exercise training, indicating that physical activity produced beneficial effects on the endothelium of epicardial coronary arteries. Physical exercise has also been associated with an increase in mediator antagonists of blood flow velocity. Final regression in coronary lesions and collateral flow recruitment, unlikely to occur within a 4-week period, were attenuated. Kruk³⁵ showed the positive effects of physical activity and improved myocardial perfusion, pointing out the potential beneficial role of therapeutic exercise training for patients with cardiovascular disease.³⁵

In another study, it was demonstrated that regular aerobic exercise can prevent the loss, as well as restore previous levels, of endothelium-dependent vasodilation in sedentary elderly and middle-aged men.³⁶ In men submitted to aerobic exercise training, endothelium-dependent vasodilation was not preserved when compared to their sedentary peers.³⁷

Clarkson et al.³⁸ found positive results in a 10-week aerobic and anaerobic exercise training program in healthy male military recruits. Gokce et al.³⁹ also found a significant increase in endothelium-dependent vasodilation in the posterior tibial artery after 10 weeks of moderate aerobic exercise training, with positive results mainly in the lower limbs.

Higashi et al.⁴⁰ analyzed hypertensive individuals submitted to a 12-week aerobic exercise training program (30 minutes, 5 to 7 times per week) and found a significant increase in endothelium-dependent vasodilation in response to acetylcholine. Individuals who had suffered a myocardial infarction were submitted to a 3-month aerobic physical training program (cycle ergometer), exercising at 75% of maximum exercise heart rate, and also showed increased endothelium-dependent vasodilation. However, after 1 month of detraining, the benefits disappeared. Such results suggest that individuals with a history of cardiac events may improve endothelial function.⁴¹

Goto⁴² analyzed the effects of different aerobic exercise intensities on the arteries and verified that moderate-intensity exercise (50% VO₂ max) was the only intensity rate capable of improving endothelium-dependent vasodilation. Low-intensity (25% VO₂ max) and high-intensity (75% VO₂ max) exercises failed to promote any benefits to endothelial function. High-intensity exercise increased oxidative stress, an injurious aspect to the arterial wall. For this reason, moderate-intensity exercise seems to be the most appropriate indication for sedentary individuals in search of cardiovascular benefits through regular aerobic exercising.

A study conducted by Umpierre & Stein,⁴³ with healthy elderly and middle-aged men randomized for resistance training for 13 weeks, showed a significant increase in blood flow and vascular conductance in the femoral artery. In type 2 diabetic db/db and normoglycemic knockout mice submitted to moderate-intensity exercise, physical training could reverse diabetic vascular endothelial dysfunction, regardless of a reduction in body weight or hyperglycemic status.⁴⁴ Although several investigators have shown that regular aerobic exercise improves endothelium-dependent vasodilation, the extent to which training is responsible for these changes remains unknown.⁴⁵

Increased aerobic exercise capacity (VO₂ max) was associated with increased arterial diameter (r = 0.66 p < 0.002) during hyperemic response in older endurance-trained men (68.5±2.3 years old) compared to older sedentary men (64.7±1.4 years old).⁴⁶ This association resulted from a higher endothelium-dependent vasodilation capacity in individuals training at least 3 times per week for at least 1 hour per day. It has been demonstrated that physical training in patients with stable coronary artery disease promotes a reduction of 49% in angiotensin II-induced vasoconstriction. Such adaptation is followed by a decreased AT1 receptor expression and an increased AT2 receptor expression.⁴⁷

The World Health Organization recommends moderate-intensity aerobic physical activity to promote good health, but such recommendantion requires a better understanding of moderate-intensity exercise-mediated antiinflammatory effects. Markovitch et al.⁴⁸ demonstrated that acute moderate-intensity exercise (50% VO₂ max) does not cause significant changes in circulating neutrophils, monocytes or in serum cytokine, such as interleukin-6, interleukin-10 and C-reactive protein, concentration after 7 continuous days of exercise in healthy adult men (54±4 years old). These results indicate that acute moderate-intensity exercise may not lead to the beneficial effects found in studies with chronic moderate-intensity exercise training program as observed in the investigations herein cited and as recommended by the World Health Organization.

As previously described, aerobic training enhances and restores endothelium-dependent vasodilation, regardless of effort type and intensity.

Final considerations

In this brief review, we could observe a direct effect of trans fatty acids on endothelial cell activation and function, although the mechanisms through which such isomers cause endothelial cell dysfunction remain unclear. Physical exercise has been considered a therapeutic intervention, revealing a positive correlation between exercise training and increased endothelium-dependent vasodilation. The mechanisms through which physical activity affects this increase in endothelium-dependent vasodilation remain unknown. Further studies on this theme should be conducted to determine the mechanism of action of trans fatty acids leading to endothelial cell dysfunction and the possible therapeutic effect of the practice of physical activity on endothelial tissue for the prevention or regression of atherosclerosis.

Acknowledgements

We thank CNPq, CAPES and FAPESP for grant support. Some passages were changed as suggested by Professor Rui Curi.

References

1. Landmesser U, Horning B, Drexler H. Endothelial function: a critical determinant in atherosclerosis? Circulation. 2004;109:II27-33.
2. Szmitko PE, Wang CH, Weisel RD, de Almeida JR, Anderson TJ, Verma S. New markers of inflammation and endothelial cell activation. Part I. Circulation. 2003;108:1917-23.
3. Steinberg D. A critical look at the evidence for the oxidation of LDL in atherogeneses. Atherosclerosis. 1997;131 Suppl:S5-7.
4. Mattern HM, Hardin CD. Vascular metabolic dysfunction and lipotoxicity. Physiol Res. 2007;56:149-58.
5. Stender S, Dyerberg J. Influence of trans fatty acids on health. Ann Nutr Metab. 2004;48:61-6.
6. Jorge PA, Osaki MP, de Almeida E, Cledídio Neto L, Metze K. Effects of vitamin E on endothelium-dependent coronary flow in hypercholesterolemic dogs. Atherosclerosis. 1996;126:43-51.
7. Grundy SM, Denke MA. Dietary influences on serum lipids and lipoproteins. J Lipid Res. 1990;31:1149-72.
8. Shaw DI, Hall WL, Jeffs NR, Williams CM. Comparative effects of fatty acids on endothelial gene expression. Eur J Nutr. 2007;46:321-8.
9. Bartus M, Lomnicka M, Lorkowska B, et al. Hypertriglyceridemia but not hypercholesterolemia induces endothelial dysfunction in the rat. Pharmacol Rep. 2005;57 Suppl:127-37.
10. Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003;23:168-75.
11. Schaffer JE. Lipotoxicity: when tissues overeat. Curr Opin Lipidol. 2003;14:281-7.
12. Emken EA. Nutrition and biochemistry of trans and positional fatty acid isomers in hydrogenated oils. Annu Rev Nutr. 1984;4:339-76.
13. Kraft J, Collomb M, Mockel P, Sieber R, Jahreis G. Differences in CLA isomer distribution of cow's milk lipids. Lipids. 2003;38:657-64.
14. Aro A, Pietinen P, Valsta LM, et al. Effects of reduced-fat diets with different fatty acid compositions on serum lipoprotein lipids and apolipoproteins. Public Health Nutr. 1998;1:109-16.
15. Dyerberg J, Eskesen DC, Andersen PW, et al. Eur J Clin Nutr. 2004;58:1062-70.
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29. Toborek M, Barger SW, Mattson MP, Barve S, McClain CJ, Hennig B. Linoleic acid and TNF-a cross-amplify oxidative injury and dysfunction of endothelial cells. J Lipid Res. 1996;37:123-35.
30. Hennig B, Shasby DM, Spector AA. Exposure to fatty acid increases human low density lipoprotein transfer across cultured endothelial monolayers. Circul Res. 1985;57:776-80.
31. Hennig B, Meerarani P, Ramadass P, Watkins BA, Toborek M. Fatty acid-mediated activation of vascular endothelial cells. Metabolism. 2000;49:1006-13.
32. Hennig B, Shasby DM, Fulton AB, Spector AA. Exposure to free fatty acid increases the transfer of albumin across cultured endothelial monolayers. Arterosclerosis. 1984;4:489-97.
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34. Hambrecht R, Hilbrich L, Erbs S, et al. J Am Coll Cardiol. 2000;35:706-13.
35. Kruk J. Asian Pac J Cancer Prev. 2007;8:325-38.
36. De Souza CA, Shapiro LF, Clevenger CM, et al. Regular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men. Circulation. 2000;102:1351-7.
37. Galleta F, Franzoni F, Virdis A, et al. Endothelium-dependent vasodilation and carotid artery wall remodeling wall in athletes and sedentary subjects. Atherosclerosis. 2006;186:184-92.
38. Clarkson P, Montgomery HE, Mullen MJ, et al. Exercise training enhances endothelium function in young men. J Am Coll Cardiol. 1999;33:1379-85.
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Correspondência:

Laureane Nunes Masi

Avenida Prof. Lineu Prestes, 1524, sala 105

Instituto de Ciências Biomédicas I, Cidade Universitária, Butantã

CEP 05508-900 São Paulo, SP

Tel.: (11) 3091.7245, Fax: (11) 3901.7285

E-mail:

laure_masi@hotmail.com

Publication Dates

Publication in this collection
02 Oct 2009
Date of issue
June 2009

History

Accepted
06 Mar 2009
Received
10 Oct 2008

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Landmesser U, Horning B, Drexler H. Endothelial function: a critical determinant in atherosclerosis? Circulation. 2004;109:II27-33.

[2] 2. Szmitko PE, Wang CH, Weisel RD, de Almeida JR, Anderson TJ, Verma S. New markers of inflammation and endothelial cell activation. Part I. Circulation. 2003;108:1917-23.

[3] 3. Steinberg D. A critical look at the evidence for the oxidation of LDL in atherogeneses. Atherosclerosis. 1997;131 Suppl:S5-7.

[4] 4. Mattern HM, Hardin CD. Vascular metabolic dysfunction and lipotoxicity. Physiol Res. 2007;56:149-58.

[5] 5. Stender S, Dyerberg J. Influence of trans fatty acids on health. Ann Nutr Metab. 2004;48:61-6.

[6] 6. Jorge PA, Osaki MP, de Almeida E, Cledídio Neto L, Metze K. Effects of vitamin E on endothelium-dependent coronary flow in hypercholesterolemic dogs. Atherosclerosis. 1996;126:43-51.

[7] 7. Grundy SM, Denke MA. Dietary influences on serum lipids and lipoproteins. J Lipid Res. 1990;31:1149-72.

[8] 8. Shaw DI, Hall WL, Jeffs NR, Williams CM. Comparative effects of fatty acids on endothelial gene expression. Eur J Nutr. 2007;46:321-8.

[9] 9. Bartus M, Lomnicka M, Lorkowska B, et al. Hypertriglyceridemia but not hypercholesterolemia induces endothelial dysfunction in the rat. Pharmacol Rep. 2005;57 Suppl:127-37.

[10] 10. Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003;23:168-75.

[11] 11. Schaffer JE. Lipotoxicity: when tissues overeat. Curr Opin Lipidol. 2003;14:281-7.

[12] 12. Emken EA. Nutrition and biochemistry of trans and positional fatty acid isomers in hydrogenated oils. Annu Rev Nutr. 1984;4:339-76.

[13] 13. Kraft J, Collomb M, Mockel P, Sieber R, Jahreis G. Differences in CLA isomer distribution of cow's milk lipids. Lipids. 2003;38:657-64.

[14] 14. Aro A, Pietinen P, Valsta LM, et al. Effects of reduced-fat diets with different fatty acid compositions on serum lipoprotein lipids and apolipoproteins. Public Health Nutr. 1998;1:109-16.

[15] 15. Dyerberg J, Eskesen DC, Andersen PW, et al. Eur J Clin Nutr. 2004;58:1062-70.

[16] 16. Woodside JV, McKinley MC, Young IS. Saturated and trans fatty acids and coronary heart disease. Curr Ather Rep. 2008;10:460-6.

[17] 17. Lopez-Garcia E, Schulze MB, Meigs JB, et al. Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction. J Nutr. 2005;135:562-6.

[18] 18. Stampfer MJ, Sacks FM, Salvini S, Willett WC, Hennekens CH. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med. 1991;325:373-81.

[19] 19. Ascherio A, Katan MB, Zock PL, Stampfer MJ, Willett WC. trans fatty acids and coronary heart disease. N Engl J Med. 1999;340:1994-8.

[20] 20. Katan MB. Regulation of trans fats: the gap, the Polder, and McDonald's French fries. Atheroscler Suppl. 2006;7:63-6.

[21] 21. Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr. 2003;77:1146-55.

[22] 22. Kuhn N, Willet A. [Nursing in Europe-Luxemborg: developing and utilizing new nursing fields]. Pflege Z. 2006;59:182-5.

[23] 23. Hennig B, Alvarado A, Ramasamy S, Boissonneault GA, Decker E, Means WJ. Fatty acid induced disruption of endothelial barrier function in culture. Biochem Arch. 1990;6:409-17.

[24] 24. Hennig B, Toborek M, McClain CJ, Diana JN. Nutritional implications in vascular endothelial cell metabolism. J Am Coll Nutr. 1996;15:345-58.

[25] 25. Mozaffarian D, Rimm EB, King IB, Lawler RL, McDonald GB, Levy WC. trans fatty acids and systemic inflammation in heart failure. Am J Clin Nutr. 2004;80:1521-5.

[26] 26. de Roos NM, Bots ML, Katan MB. Replacement of dietary saturated fatty acids by trans fatty acids lowers serum HDL cholesterol and impairs endothelial function in healthy men and women. Arterioscler Thromb Vasc Biol. 2001;21:1233-7.

[27] 27. Kinsella JE, Bruckner G, Mai J, Shimp J. Metabolism of trans fatty acids with emphasis on the effects of trans, trans-octadecadienoate on lipid composition, essential fatty acid, and prostaglandins: an overview. Am J Clin Nutr. 1981;34:2307-18.

[28] 28. Kummerow FA, Zhou Q, Mahfouz MM, Smiricky MR, Grieshop CM, Schaeffer DJ. trans fatty acids in hydrogenated fat inhibited the synthesis of the polyunsaturated fatty acids in the phospholipid of arterial cells. Life Sci. 2004;74:2707-23.

[29] 29. Toborek M, Barger SW, Mattson MP, Barve S, McClain CJ, Hennig B. Linoleic acid and TNF-a cross-amplify oxidative injury and dysfunction of endothelial cells. J Lipid Res. 1996;37:123-35.

[30] 30. Hennig B, Shasby DM, Spector AA. Exposure to fatty acid increases human low density lipoprotein transfer across cultured endothelial monolayers. Circul Res. 1985;57:776-80.

[31] 31. Hennig B, Meerarani P, Ramadass P, Watkins BA, Toborek M. Fatty acid-mediated activation of vascular endothelial cells. Metabolism. 2000;49:1006-13.

[32] 32. Hennig B, Shasby DM, Fulton AB, Spector AA. Exposure to free fatty acid increases the transfer of albumin across cultured endothelial monolayers. Arterosclerosis. 1984;4:489-97.

[33] 33. Harvey KA, Arnold T, Rasool T, Antalis C, Miller SJ, Siddiqui RA. trans-fatty acids induce pro-inflammatory responses and endothelial cell dysfunction. Br J Nutr. 2008;99:723-31.

[34] 34. Hambrecht R, Hilbrich L, Erbs S, et al. J Am Coll Cardiol. 2000;35:706-13.

[35] 35. Kruk J. Asian Pac J Cancer Prev. 2007;8:325-38.

[36] 36. De Souza CA, Shapiro LF, Clevenger CM, et al. Regular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men. Circulation. 2000;102:1351-7.

[37] 37. Galleta F, Franzoni F, Virdis A, et al. Endothelium-dependent vasodilation and carotid artery wall remodeling wall in athletes and sedentary subjects. Atherosclerosis. 2006;186:184-92.

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