Omega-3, Omega-6 and Omega-9 Fatty Acids: Implications for Cardiovascular and Other Diseases
Melissa Johnson1* and Chastity Bradford2
1College of Agriculture, Environment and Nutrition Sciences, Tuskegee University, Tuskegee, Alabama, USA
2Department of Biology, Tuskegee University, Tuskegee, Alabama, USA
- *Corresponding Author:
- Melissa Johnson
College of Agriculture
Environment and Nutrition Sciences
Tuskegee University, Tuskegee
E-mail: [email protected]
Received date: September 02, 2014; Accepted date: September 26, 2014; Published date: September 30, 2014
Citation: Johnson M, Bradford C (2014) Omega-3, Omega-6 and Omega-9 Fatty Acids: Implications for Cardiovascular and Other Diseases. J Glycomics Lipidomics 4:123. doi: 10.4172/2153-0637.1000123
Copyright: © 2014 Johnson M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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The relationship between diet and disease has long been established, with epidemiological and clinical evidence affirming the role of certain dietary fatty acid classes in disease pathogenesis. Within the same class, different fatty acids may exhibit beneficial or deleterious effects, with implications on disease progression or prevention. In conjunction with other fatty acids and lipids, the omega-3, -6 and -9 fatty acids make up the lipidome, and with the conversion and storage of excess carbohydrates into fats, transcendence of the glycome into the lipidome occurs. The essential omega-3 fatty acids are typically associated with initiating anti-inflammatory responses, while omega-6 fatty acids are associated with pro-inflammatory responses. Non-essential, omega-9 fatty acids serve as necessary components for
other metabolic pathways, which may affect disease risk. These fatty acids which act as independent, yet synergistic lipid moieties that interact with other biomolecules within the cellular ecosystem epitomize the critical role of these fatty acids in homeostasis and overall health. This review focuses on the functional roles and potential mechanisms of omega-3, omega-6 and omega-9 fatty acids in regard to inflammation and disease pathogenesis. A particular emphasis is placed on cardiovascular disease, the leading cause of morbidity and mortality in the United States.
Omega-3 fatty acids; Omega-6 fatty acids; Omega-9 fatty acids; Cardiovascular disease; Hypertension; Inflammation
Strategic in pathophysiological homeostasis (following injury), as well as cellular, tissue and organismic protection are acute and chronic inflammatory responses [1,2]. Consequently, the pathogenesis and progression of cardiovascular and other diseases is initiated and perpetuated by this phenomenon. Efforts to normalize or control inflammatory processes include pharmacological, dietary and behavioral therapies, aimed at regulating biologically stimulatory molecules that may stimulate or suppress the synthesis of inflammatory triggers and subsequent byproducts [3-9]. The most recognizable potent bioactive lipid mediators are Arachidonic Acid (AA, C20:4n6), Eicosapentaenoic Acid (EPA, C22:5n3) and Docosahexaenoic Acid (DHA, C20:6n3), synthesized from their dietarly essential precursors linoleic (LA, C18:3n6) and α- linolenic (ALA, C18:3n3) acids (Figure 1). The omega-9 fatty acid, oleic acid, has been suggested to occupy a role in the metabolism of the essential fatty acids [10,11]. These bioactive lipid mediatorsregulate pro-and anti-inflammatory processes via their ability to stimulate enzymes and produce cytokines and other acute phase molecules . Further, these mediators occupy a central role in the synthesis of lipoxins and resolvins that hinder inflammatory pathways, increase the production of anti-inflammatory cytokines and facilitate the resolution of acute inflammation [13-17]. Decreasing dietaryomega-6 fatty acid (i.e. linoleic acid) intake increases the bioavailability of omega-3 fatty acids , which may in turn lower tissue concentrations of the omega-6/omega-3 fatty acid ratio, mitigate the intensity and duration of inflammatory responses and subsequently reduce disease risk [19-21].
Figure 1: Summary of omega-3, omega-6 and omega-9 fatty acid metabolism and implications for disease.
The relationship between omega-3 and omega-6 fatty acids, inflammation and disease pathogenesis continues to be a topic of extensive study. To a lesser magnitude omega-9 fatty acids have been considered as potential disease mediators. These fatty acids may work individually, additively or synergistically as precursors and critical elements within metabolic pathways, thus actively influencing and/ or altering membrane fluidity, cell structure, and disease pathogenesis (Table 1). Research has revealed the relationship between inflammation and the cellular lipidomic (i.e. lipid) and glycomic (i.e. sugar) profiles, genetic regulation and signaling, suggesting that these profiles may be useful clinical diagnostic and therapeutic tools [22-57]. This review provides a brief synopsis of the structure, function and physiological implications of the omega-3, omega-6 and omega-9 fatty acids in inflammation, hypertension, and Cardiovascular Disease (CVD).
|Omega-3 Fatty Acids
|α-linolenic acid, ALA
- linseed oil, kiwifruit oil, chia seed oil, flaxseed oil, canola (rapeseed) oil, soybean, purslane, walnuts
|↓ oxidative stress
↓ platelet aggregation
|Eicosapentaenoic acid, EPA
||Oily fish, fish oil, certain seaweeds, human breast milk
improved insulin sensitivity
|↓ oxidative stress
|Docosahexaenoic acid, DHA
||Cold water fish,
metabolic synthesis from EPA
|↓ decline in mental
↑ visual acuity
↓ colon carcinoma cell growth
|Omega-6 Fatty Acids
|Linoleic acid, LA
||Corn, peanut, soybean, cottonseed, other plant oils
||↑ vascular adhesion molecule-1 expression
||Meat, eggs, dairy products
||↑ platelet aggregation
↑ eicosanoid synthesis
↑ vascular damage
↑ oxidative stress
|Omega-9 Fatty Acids
||Olive oil, macadamia oil
|↓ LDL cholesterol
↓ LDL cholesterol oxidation
improved lipid profile
||King salmon, yellow mustard seed, flaxseed
||nerve cell myelin biosynthesis
||↓ obesity-related risk factors for CVD
Table 1: Structure, dietary source, mechanism and implications of select omega-3, omega-6 and omega-9 fatty acids.
Omega fatty acids and inflammation
Inflammation,resulting from various genetic, demographic, behavioral, environmental and nutritional interactions, is at the center of CVDand other vascular diseases (Figure 2). Potential triggers of increased risk for inflammation and subsequent endothelial and vascular injury are genetic characteristics , Western dietary patterns , environmental toxins , adaptive immune responses , the presence of other co-morbidities [62,63], and socioeconomic factors . This is evident in the new paradigm shift of evaluation of heart failure patients with preserved ejection fraction. The emphasis shifts from solely using left ventricular afterload to evaluate heart failure patients, and now includes coronary microvascular inflammation  thus, changing the methods of patient evaluation. Omega fatty acids have been described as inflammation-modulating agents, which may stimulate or suppress the synthesis of pro- and/or anti-inflammatory cell signaling molecules. In a recent randomized controlled trial, omega-3 polyunsaturated fatty acid supplementation lowered the concentration of serum proinflammatory cytokines.
Figure 2: Interactions between and among factors contributing to inflammatory status and disease risk.
One of the omega-6 fatty acids, arachidonic acid, directly impacts inflammation. In vitro it enhanced the ability of endothelial cells to bind monocytes- thus,facilitating the pro-inflammatoryprocess. Linoleic and γ-linolenic, omega-6 fatty acids, and omega-9 oleic acids were able to indirectly provoke the synthesis of Reactive Oxygen Species (ROS) superoxide, a pro-inflammatory mediator, mainly by activating p47 and NADPH oxidase enzyme complex . Oleic acid also induced foam cell formation in rat aorta smooth muscle cells and enhanced atherosclerotic lesion development . This is of particular interest as macrophage foam cell has been suggested to be a potential target for therapeutic interventions , with the oxidative byproducts of cholesterol metabolism being found to influence the lipidome and transcriptome of the macrophage . Others found the activation of macrophagesto regulate the expression of genes involved in lipid metabolism, immunity and apoptosis [71,72].
An alternative study found that oleic acid exerted vascular antiatherogenic effects  Oleic acid was able to mitigate the effects of TNF-α-induced oxidative stress and injury in adult male Sprague- Dawley rat cardiomyocytes  as well as reduce the inflammation associated with saturated fatty acid-induced inflammation in human aortic endothelial cells . Further, the incorporation of milks enriched with oleic acid into the diet has resulted in reductions in total cholesterol, LDL-cholesterol and triglyceride levels, the effects of which were observed among healthy individuals, those with increased risk for cardiovascular disease and individuals with CVD . Although studied to a much lesser degree than oleic acid, another omega-9 fatty acid, nervonic acid, has demonstrated influence on CVD risk. Researchers found Body Mass Index (BMI), leptin, triglycerides, total cholesterol and fasting blood glucose to be significantly negatively correlated with serum nervonic acid..These findings illustrate the ability of nervonic acid to exert protective effects against obesogeniclinked risk factors and conditions such as insulin resistance, diabetes, dyslipidemia and metabolic syndrome.
The impact of fatty acids as inflammatory-modulators is crucial to the state of the vasculature.The vasculature is mainly comprised of endothelial cells, caveolae, smooth muscle cells, adventitia, and fibroblasts. Thus, the cellular responsiveness of the vasculature is vital to the endothelium.The endothelial cells are in direct contact with the red blood cells, and blood lipid profiles are tools of evaluating cardiovascular health. Fatty acid composition of a major component of the endothelium, caveolae, played a regulatory role in TNF-α- induced endothelial cell activation and inflammation. The major omega-6 unsaturated fatty acids in the American diet are atherogenic and enhance the endothelial inflammatory response . One of them, arachidonic acid, directly impacted inflammation. In vitro, it enhanced the ability of endothelial cells to bind, a pro-inflammatory response . In younger animals, estrogen inhibits the expression of proinflammatory mediators in vascular smooth muscle cells . Therefore, in addition to the fatty acids, age and gender play a major role in the inflammatory response.Further, a higher eicosapentaenoic acid to arachidonic acid ratio was associated with decreased LV wall thickness among individuals with diabetes . The ability ofomega-3, 6, and 9 fatty acids to differentially modulate inflammatory stimuli, impact vascular composition,cellular responsiveness, and influence the structural integrity of the left ventricle underscore the implications of these fatty acids in chronic disease risk and prevention.
Omega fatty acids and hypertension
Chronic diseases such as hypertension, obesity, and diabetes are a national and international concern.Obesity prevalence has increased dramatically in recent years. The mortality of obese patients is more often a result of diabetes and hypertension . Obesity is strongly associated with metabolic abnormalities, including insulin resistance, type 2 diabetes, hypertension, and dyslipidemia, mediated in part by the chronic inflammatory state induced by the secretion of adipocytokines, such as angiotensinogen, transforming growth factor–beta, tumor necrosis factor–alpha, and interleukin-six [81-83].
The cardioprotective mechanisms of the omega-3 fatty acids Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) have been attributed to their ability to displace the omega-6 fatty acid, arachidonic acid , as molecular substrates during the cyclooxygenase and oxygenase pathways. The combined hypotensive effects of EPA and DHA have been demonstrated in randomized controlled trials . However others found DHA and DHA epoxides to be effective in lowering blood pressure but not EPA . The epoxides of an omega-6 fatty acid, arachidonic acid epoxyeicosatrienoic acids also exhibit antihypertensive and anti-inflammatory effects . Actions of these fatty acids subsequently influence metabolism, β-oxidation, fatty acid synthesis, pro-inflammatory molecule synthesis and the transcription of genes coding for transcription factors (e.g. Peroxisome Proliferator-Activated Receptor [PPAR], Sterol-Response Element Binding Protein [SREBP] and Nuclear Factor jB [NF-jB] as well as enzymes implicated in cholesterol synthesis) [87,88]. Intake of EPA and DHA has been inversely associated with markers of inflammation in both men and women  In addition to influencing cytokine concentrations, EPA and DHA have been demonstrated to influence blood glucose and lipid profile . The supplementation of DHA into the diet of hypertriglycemic men was found to decrease serum levels of c-reactive protein and other inflammatory biomarkers .
Studies suggest that there is a role for the renin-angiotensin system in the mechanistic blood pressure lowering effects of omega-3 fatty acids.The Ren-2 rat model is mediated by ANG II, and the data suggest that omega-3 PUFA may reduce hypertension via the renin-angiotensin system . In models of Angiotensin-II induced hypertension, DHA epoxides reduce inflammation and systolic blood pressure partially via reduction of prostaglandins, MCP-1, and upregulation of angiotensin-converting enzyme-2. It has been proposed that the oleicacid constituent of olive oil may be responsible for the hypotensive and cardio protectiveeffect associated with olive oil consumption [93-96]. Flaxseed, one of the richest sources of the plant-based omega-3 fatty acid, alpha-linolenic acid has been suggested to have a positive impact on CVD.There is strong scientific evidence from human trials that omega-3 fatty acids from fish or fish oil supplements (EPA and DHA) can significantly reduce risk factors for heart disease (such as reducing blood triglyceride [TG] levels, LDL-cholesterol, serum lipids, blood glucose), diabetes and metabolic syndrome [97-100], yet using nutritional strategies to combat diseases is not the first line of therapeutic intervention [101,102]. Unfortunately, analysis of national observational data indicates that U.S. adults are not consuming the recommended intake of fish and omega-3 fatty acids .
Omega fatty acids and other diseases
In addition to suppressing or inhibiting the expression of specific genes implicated in lipid metabolism, dietary fatty acid intake influences cellular, molecular oxidative and inflammatory status . In addition to occupying a role in immune function , oleic acid inhibits food intake and glucose production in male rats  and has been suggested to enhance insulin production in rat pancreatic beta cells in both in vivo and in vitro environments favoring the inhibition of insulin production by TNF-α . Further, the presence of a rich supply of oleic acid within low density lipoprotein molecules was protective against oxidative modification in rabbits, suggesting the antiatherogenic propensity of oleic acid. Conversely oleic acid was able to facilitate increased macrophage concentrations in mesenteric adipose tissue  and attenuate renal fibrosis . Although omega-3 fatty acids have been classified as anti-inflammatory mediators, there is conflicting evidence on the definite ability of these fatty acids to consistently reduce the risks, morbidities and mortalities associated with CVD, cancers and other inflammatory diseases and disorders . There is also evidence for the role of omega-3 fatty acids in the stress response and cognitive function.Rats fed the omega-3 enriched diet had a lower stress-induced weight loss and plasma corticosterone peak, and reduced grooming . These data suggest that the response to chronic restraint stress can also be altered by omega-3 fatty acids.
Central to the initiation, pathogenesis and progression of many disease states is inflammation. Conventional mechanisms of alleviating inflammation include pharmacological therapies, which often target specific key components of inflammatory pathways. Albeit not relatively novel, increased attention has been devoted to more aggressively reevaluating dietary approaches that mitigate inflammatory sequelae. Serving as mediators of lipid metabolism and foundational biomolecules of the lipidome, the character of omega-3, omega-6 and omega-9 fatty acids warrants further discussion. Omega-3 and omega-6 fatty acids have typically been associated with anti- and pro-inflammatory pathways, respectively, whereas the direct role of omega-9 fatty acids in inflammatory pathways remains unclear. In conjunction with other fatty acids and lipid classes, the omega-3, -6 and -9 fatty acids make up the lipidome, and within the conversion of excess carbohydrates into fats, transcendence of the glycome into the lipidome occurs.
More recently, lipidomics profiling has been used as an assessment and monitoring tool for cardiovascular and other disease risk [23,111]. Bioinformatical tools have been particularly useful in examining the lipidome . The genetic, metabolic and phenotypic consequences of omega-3, omega-6 and omega-9 fatty acids range from undetectable to detectable, and may even endure throughout subsequent cellular and organismic generations (Figure 3). Although research affirms a relationship between omega-3, omega-6 and omega-9 fatty acids, both synergistically with the metabolism of the other fatty acids, as well as individually in modulating specific pathways, findings are conflicting.Together the anti-inflammatory exertions, along with the pro-inflammatory mechanisms, highlight the delicate, oftentimes calculated mercurial nature of these fatty acids in maintaining homeostasis. Additional research is needed to add credence to the emergence of omega-3, omega-6 and omega-9 fatty acids as modulators of metabolism, lipidomics and glycomics.
Figure 3: Potential cellular, molecular and genetic interactions and implications of omega-3, omega-6 and omega-9 fatty acids on biological systems and health/ disease outcomes.
This work was supported by the Tuskegee University College Agriculture, Environment and Nutrition Sciences, the George Washington Carver Experiment Station and the Tuskegee University College of Arts and Sciences (Tuskegee, AL).
- Libby P (2007) Inflammatory mechanisms: the molecular basis of inflammation and disease. Nutr Rev 65: S140-146.
- Tabas I, Glass CK (2013) Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339: 166-172.
- Hengge UR, Benninghoff B, Ruzicka T, Goos M (2001) Topical immunomodulators--progress towards treating inflammation, infection, and cancer. Lancet Infect Dis 1: 189-198.
- Klingenberg R, Hansson GK (2009) Treating inflammation in atherosclerotic cardiovascular disease: emerging therapies. Eur Heart J 30: 2838-2844.
- Charo IF, Taub R (2011) Anti-inflammatory therapeutics for the treatment of atherosclerosis. Nat Rev Drug Discov 10: 365-376.
- Weber C, Noels H (2011) Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 17: 1410-1422.
- Wu X, Schauss AG (2012) Mitigation of inflammation with foods. J Agric Food Chem 60: 6703-6717.
- Renaud HJ, Cui JY, Lu H, Klaassen CD (2014) Effect of diet on expression of genes involved in lipid metabolism, oxidative stress, and inflammation in mouse liver-insights into mechanisms of hepatic steatosis. PLoS One 9: e88584.
- Saneei P, Hashemipour M, Kelishadi R, Esmaillzadeh A (2014) The Dietary Approaches to Stop Hypertension (DASH) diet affects inflammation in childhood metabolic syndrome: a randomized cross-over clinical trial. Ann NutrMetab 64: 20-27.
- DhopeshwarkarGA,Mead JF (1961) Role of oleic acid in the metabolism of essential fatty acids. Journal of the American Oil Chemists Society 38: 297-301.
- Lowry RR, Tinsley IJ (1966) Oleic and linoleic acid interaction in polyunsaturated fatty acid metabolism in the rat. J Nutr 88: 26-32.
- Maskrey BH, Megson IL, Whitfield PD, Rossi AG (2011) Mechanisms of resolution of inflammation: a focus on cardiovascular disease. ArteriosclerThrombVascBiol 31: 1001-1006.
- Serhan CN, Savill J (2005) Resolution of inflammation: the beginning programs the end. Nat Immunol 6: 1191-1197.
- Schwab JM, Serhan CN (2006) Lipoxins and new lipid mediators in the resolution of inflammation. CurrOpinPharmacol 6: 414-420.
- Spite M, Serhan CN (2010) Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins. Circ Res 107: 1170-1184.
- Dalli J, Colas RA, Serhan CN (2013) Novel n-3 immunoresolvents: structures and actions. Sci Rep 3: 1940.
- Aursnes M, Tungen JE, Vik A, Colas R, Cheng CY, et al. (2014) Total synthesis of the lipid mediator PD1n-3 DPA: configurational assignments and anti-inflammatory and pro-resolving actions. J Nat Prod 77: 910-916.
- Taha AY, Cheon Y, Faurot KF, Macintosh B, Majchrzak-Hong SF, et al. (2014) Dietary omega-6 fatty acid lowering increases bioavailability of omega-3 polyunsaturated fatty acids in human plasma lipid pools. Prostaglandins LeukotEssent Fatty Acids 90: 151-157.
- Simopoulos AP (2008) The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med (Maywood) 233: 674-688.
- Simopoulos A (2004) Omega-6/omega-3 essential fatty acid ratio and chronic diseases. Food Rev Int 20: 77-90.
- Simopoulos AP (2006) Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases. Biomed Pharmacother 60: 502-507.
- Angata T, Fujinawa R, Kurimoto A, Nakajima K, Kato M, et al. (2012) Integrated approach toward the discovery of glyco-biomarkers of inflammation-related diseases. Ann N Y Acad Sci 1253: 159-169.
- Meikle PJ, Wong G, Barlow CK, Kingwell BA (2014) Lipidomics: potential role in risk prediction and therapeutic monitoring for diabetes and cardiovascular disease. PharmacolTher 143: 12-23.
- Willhauck-Fleckenstein M, Moehler TM, Merling A, Pusunc S, Goldschmidt H, et al. (2010) Transcriptional regulation of the vascular endothelial glycome by angiogenic and inflammatory signalling. Angiogenesis 13: 25-42.
- Kreisman LS, Cobb BA (2012) Infection, inflammation and host carbohydrates: a Glyco-Evasion Hypothesis. Glycobiology 22: 1019-1030.
- Rodriguez-Leyva D, Dupasquier CM, McCullough R, Pierce GN (2010) The cardiovascular effects of flaxseed and its omega-3 fatty acid, alpha-linolenic acid. Can J Cardiol 26: 489-496.
- Zhao G, Etherton TD, Martin KR, West SG, Gillies PJ, et al. (2004) Dietary alpha-linolenic acid reduces inflammatory and lipid cardiovascular risk factors in hypercholesterolemic men and women. J Nutr 134: 2991-2997.
- Singer P, Jaeger W, Berger I, Barleben H, Wirth M, et al. (1990) Effects of dietary oleic, linoleic and alpha-linolenic acids on blood pressure, serum lipids, lipoproteins and the formation of eicosanoid precursors in patients with mild essential hypertension. J Hum Hypertens 4: 227-233.
- Paschos GK, Magkos F, Panagiotakos DB, Votteas V, Zampelas A (2007) Dietary supplementation with flaxseed oil lowers blood pressure in dyslipidaemic patients. Eur J ClinNutr 61: 1201-1206.
- Karvonen HM, Aro A, Tapola NS, Salminen I, Uusitupa MI, et al. (2002) Effect of alpha-linolenic acid-rich Camelina sativa oil on serum fatty acid composition and serum lipids in hypercholesterolemic subjects. Metabolism 51: 1253-1260.
- Bemelmans WJ, Muskiet FA, Feskens EJ, de Vries JH, Broer J, et al. (2000) Associations of alpha-linolenic acid and linoleic acid with risk factors for coronary heart disease. Eur J ClinNutr 54: 865-871.
- Caligiuri SP, Aukema HM, Ravandi A, Guzman R, Dibrov E, et al. (2014) Flaxseed consumption reduces blood pressure in patients with hypertension by altering circulating oxylipins via an α-linolenic acid-induced inhibition of soluble epoxide hydrolase. Hypertension 64: 53-59.
- Jang JY, Kim TS, Cai J, Kim J, Kim Y, et al. (2014) Perilla oil improves blood flow through inhibition of platelet aggregation and thrombus formation. Lab Anim Res 30: 21-27.
- Figueras M, Olivan M, Busquets S, López-Soriano FJ, Argilés JM (2011) Effects of eicosapentaenoic acid (EPA) treatment on insulin sensitivity in an animal model of diabetes: improvement of the inflammatory status. Obesity (Silver Spring) 19: 362-369.
- Kalupahana NS, Claycombe K, Newman SJ, Stewart T, Siriwardhana N, et al. (2010) Eicosapentaenoic acid prevents and reverses insulin resistance in high-fat diet-induced obese mice via modulation of adipose tissue inflammation. J Nutr 140: 1915-1922.
- Kohashi K, Nakagomi A, Saiki Y, Morisawa T, Kosugi M, et al. (2014) Effects of eicosapentaenoic acid on the levels of inflammatory markers, cardiac function and long-term prognosis in chronic heart failure patients with dyslipidemia. J AtherosclerThromb 21: 712-729.
- Aziz Jalali MH, EshraghianM,Keshavarz SA, Jazayery A, Mahmoudabadi M, et al. (2012) Inflammatory biomarkers, antioxidant enzyme activities, and oxidative stress in Iranian male patients with type 2 diabetes mellitus: Effects of eicosapentaenoic acid and vitamin C supplementation. Journal of Medical Signals and Sensors2.
- Iketani T, Takazawa K, Yamashina A (2013) Effect of eicosapentaenoic acid on central systolic blood pressure. Prostaglandins LeukotEssent Fatty Acids 88: 191-195.
- Ryan AS, Bailey-Hall E, Nelson EB, Salem N Jr (2009) Thehypolipidemic effect of an ethyl ester of algal-docosahexaenoic acid in rats fed a high-fructose diet. Lipids 44: 817-826.
- Bazan NG, Molina MF, Gordon WC (2011) Docosahexaenoic acid signalolipidomics in nutrition: significance in aging, neuroinflammation, macular degeneration, Alzheimer's, and other neurodegenerative diseases. Annu Rev Nutr 31: 321-351.
- Sagara M, Njelekela M, Teramoto T, Taguchi T, Mori M, et al. (2011) Effects of docosahexaenoic Acid supplementation on blood pressure, heart rate, and serum lipids in Scottish men with hypertension and hypercholesterolemia. Int J Hypertens 2011: 809198.
- Calon F, Lim GP, Yang F, Morihara T, Teter B, et al. (2004) Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron 43: 633-645.
- Narayanan BA, Narayanan NK, Reddy BS (2001) Docosahexaenoic acid regulated genes and transcription factors inducing apoptosis in human colon cancer cells. Int J Oncol 19: 1255-1262.
- Chapkin RS, Seo J, McMurray DN, Lupton JR (2008) Mechanisms by which docosahexaenoic acid and related fatty acids reduce colon cancer risk and inflammatory disorders of the intestine. ChemPhys Lipids 153: 14-23.
- Birch EE, Hoffman DR, Uauy R, Birch DG, Prestidge C (1998) Visual acuity and the essentiality of docosahexaenoic acid and arachidonic acid in the diet of term infants. Pediatr Res 44: 201-209.
- Hoffman DR, Boettcher JA, Diersen-Schade DA (2009) Toward optimizing vision and cognition in term infants by dietary docosahexaenoic and arachidonic acid supplementation: a review of randomized controlled trials. Prostaglandins LeukotEssent Fatty Acids 81: 151-158.
- Martinelli N, Girelli D, Malerba G, Guarini P, Illig T, et al. (2008) FADS genotypes and desaturase activity estimated by the ratio of arachidonic acid to linoleic acid are associated with inflammation and coronary artery disease. Am J ClinNutr 88: 941-949.
- Young VM, Toborek M, Yang F, McClain CJ, Hennig B (1998) Effect of linoleic acid on endothelial cell inflammatory mediators. Metabolism 47: 566-572.
- Dichtl W, Ares MP, Jönson AN, Jovinge S, Pachinger O, et al. (2002) Linoleic acid-stimulated vascular adhesion molecule-1 expression in endothelial cells depends on nuclear factor-kappaB activation. Metabolism 51: 327-333.
- Maingrette F, Renier G (2005) Linoleic acid increases lectin-like oxidized LDL receptor-1 (LOX-1) expression in human aortic endothelial cells. Diabetes 54: 1506-1513.
- IBD in EPIC Study Investigators, Tjonneland A, Overvad K, Bergmann MM, Nagel G, et al. (2009) Linoleic acid, a dietary n-6 polyunsaturated fatty acid, and the aetiology of ulcerative colitis: a nested case-control study within a European prospective cohort study. Gut 58: 1606-1611.
- Frelinger AL 3rd, Furman MI, Linden MD, Li Y, Fox ML, et al. (2006) Residual arachidonic acid-induced platelet activation via an adenosine diphosphate-dependent but cyclooxygenase-1- and cyclooxygenase-2-independent pathway: a 700-patient study of aspirin resistance. Circulation 113: 2888-2896.
- Chawengsub Y, Gauthier KM, Campbell WB (2009) Role of arachidonic acid lipoxygenase metabolites in the regulation of vascular tone. Am J Physiol Heart CircPhysiol 297: H495-507.
- Massaro M, De Caterina R (2002) Vasculoprotective effects of oleic acid: epidemiological background and direct vascular antiatherogenic properties. NutrMetabCardiovasc Dis 12: 42-51.
- Jones PJ, Senanayake VK, Pu S, Jenkins DJ, Connelly PW, et al. (2014) DHA-enriched high–oleic acid canola oil improves lipid profile and lowers predicted cardiovascular disease risk in the canola oil multicenter randomized controlled trial. Am J ClinNutr 081133.
- Parthasarathy S, Khoo JC, Miller E, Barnett J, Witztum JL, et al. (1990) Low density lipoprotein rich in oleic acid is protected against oxidative modification: implications for dietary prevention of atherosclerosis. ProcNatlAcadSci U S A 87: 3894-3898.
- Oda E, Hatada K, Kimura J, Aizawa Y, Thanikachalam PV, et al. (2005) Relationships between serum unsaturated fatty acids and coronary risk factors: negative relations between nervonic acid and obesity-related risk factors. Int Heart J 46: 975-985.
- Elliott P, Chambers JC, Zhang W, Clarke R, Hopewell JC, et al. (2009) Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA 302: 37-48.
- Giugliano D, Ceriello A, Esposito K (2006) The effects of diet on inflammation: emphasis on the metabolic syndrome. J Am CollCardiol 48: 677-685.
- Hennig B, Oesterling E, Toborek M (2007) Environmental toxicity, nutrition, and gene interactions in the development of atherosclerosis. NutrMetabCardiovasc Dis 17: 162-169.
- Greaves DR, Channon KM (2002) Inflammation and immune responses in atherosclerosis. Trends Immunol 23: 535-541.
- Lamon BD, Hajjar DP (2008) Inflammation at the molecular interface of atherogenesis: an anthropological journey. Am J Pathol 173: 1253-1264.
- Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105: 1135-1143.
- Rosvall M, Engström G, Janzon L, Berglund G, Hedblad B (2007) The role of low grade inflammation as measured by C-reactive protein levels in the explanation of socioeconomic differences in carotid atherosclerosis. Eur J Public Health 17: 340-347.
- Paulus WJ, Tschöpe C (2013) A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am CollCardiol 62: 263-271.
- Kiecolt-Glaser JK, Epel ES, Belury MA, Andridge R, Lin J, et al. (2013) Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial. Brain BehavImmun 28: 16-24.
- Hatanaka E, Dermargos A, Hirata AE, Vinolo MA, Carpinelli AR, et al. (2013) Oleic, linoleic and linolenic acids increase ros production by fibroblasts via NADPH oxidase activation. PLoS One 8: e58626.
- Ma S, Yang D, Li D, Tang B, Yang Y (2011) Oleic acid induces smooth muscle foam cell formation and enhances atherosclerotic lesion development via CD36. Lipids Health Dis 10: 53.
- Li AC, Glass CK (2002) The macrophage foam cell as a target for therapeutic intervention. Nat Med 8: 1235-1242.
- Shibata N, Carlin AF, Spann NJ, Saijo K, Morello CS, et al. (2013) 25-Hydroxycholesterol activates the integrated stress response to reprogram transcription and translation in macrophages. J Biol Chem 288: 35812-35823.
- Dinasarapu AR, Gupta S, Ram Maurya M, Fahy E, Min J, et al. (2013) A combined omics study on activated macrophages--enhanced role of STATs in apoptosis, immunity and lipid metabolism. Bioinformatics 29: 2735-2743.
- Maurya MR, Gupta S, Li X, Fahy E, Dinasarapu AR, et al. (2013) Analysis of inflammatory and lipid metabolic networks across RAW264.7 and thioglycolate-elicited macrophages. J Lipid Res 54: 2525-2542.
- Al-Shudiefat AA, Sharma AK, Bagchi AK, Dhingra S, Singal PK (2013) Oleic acid mitigates TNF-Î±-induced oxidative stress in rat cardiomyocytes. Mol Cell Biochem 372: 75-82.
- Harvey KA, Walker CL, Xu Z, Whitley P, Pavlina TM, et al. (2010) Oleic acid inhibits stearic acid-induced inhibition of cell growth and pro-inflammatory responses in human aortic endothelial cells. J Lipid Res 51: 3470-3480.
- Lopez-Huertas E (2010) Health effects of oleic acid and long chain omega-3 fatty acids (EPA and DHA) enriched milks. A review of intervention studies. Pharmacol Res 61: 200-207.
- Wang L, Lim EJ, Toborek M, Hennig B (2008) The role of fatty acids and caveolin-1 in tumor necrosis factor alpha-induced endothelial cell activation. Metabolism 57: 1328-1339.
- Grenon SM, Aguado-Zuniga J, Hatton JP, Owens CD, Conte MS, et al. (2012) Effects of fatty acids on endothelial cells: inflammation and monocyte adhesion. J Surg Res 177: e35-43.
- Bowling MR, Xing D1, Kapadia A1, Chen YF1, Szalai AJ1, et al. (2014) Estrogen effects on vascular inflammation are age dependent: role of estrogen receptors. ArteriosclerThrombVascBiol 34: 1477-1485.
- Okamoto K, Sato A, Matsukawa K, Kasuga T, Uchigata Y (2014) Impact of eicosapentaenoic acid/arachidonic acid ratio on left ventricular structure in patients with diabetes. DiabetologyInt 1-9.
- Kitahara CM, Flint AJ, Berrington de Gonzalez A, Bernstein L, Brotzman M, et al. (2014) Association between class III obesity (BMI of 40-59 kg/m2) and mortality: a pooled analysis of 20 prospective studies. PLoS Med 11: e1001673.
- Nikolopoulou A, Kadoglou NP (2012) Obesity and metabolic syndrome as related to cardiovascular disease. Expert Rev CardiovascTher 10: 933-939.
- Cottam DR, Mattar SG, Barinas-Mitchell E, Eid G, Kuller L, et al. (2004) The chronic inflammatory hypothesis for the morbidity associated with morbid obesity: implications and effects of weight loss. ObesSurg 14: 589-600.
- Vinciguerra F, Baratta R, Farina MG, Tita P, Padova G, et al. (2013) Very severely obese patients have a high prevalence of type 2 diabetes mellitus and cardiovascular disease. ActaDiabetol 50: 443-449.
- Miller PE, Van Elswyk M2, Alexander DD3 (2014) Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and blood pressure: a meta-analysis of randomized controlled trials. Am J Hypertens 27: 885-896.
- Mori TA, Bao DQ, Burke V, Puddey IB, Beilin LJ (1999) Docosahexaenoic acid but not eicosapentaenoic acid lowers ambulatory blood pressure and heart rate in humans. Hypertension 34: 253-260.
- Ulu A, Harris TR, Morisseau C, Miyabe C, Inoue H, et al. (2013) Anti-inflammatory effects of Ï‰-3 polyunsaturated fatty acids and soluble epoxide hydrolase inhibitors in angiotensin-II-dependent hypertension. J CardiovascPharmacol 62: 285-297.
- Komprda T (2012) Eicosapentaenoic and docosahexaenoic acids as inflammation-modulating and lipid homeostasis influencing nutraceuticals: A review. J Funct Foods 4: 25-38.
- Harmon GS, Lam MT, Glass CK (2011) PPARs and lipid ligands in inflammation and metabolism. Chem Rev 111: 6321-6340.
- Pischon T, Hankinson SE, Hotamisligil GS, Rifai N, Willett WC, et al. (2003) Habitual dietary intake of n-3 and n-6 fatty acids in relation to inflammatory markers among US men and women. Circulation 108: 155-160.
- Raghu B, Venkatesan P (2008) Effect of n-3 fatty acid supplementation on blood glucose, lipid profile and cytokines in humans: A pilot study. Indian J Clin Biochem 23: 85-88.
- Kelley DS, Siegel D, Fedor DM, Adkins Y, Mackey BE (2009) DHA supplementation decreases serum C-reactive protein and other markers of inflammation in hypertriglyceridemic men. J Nutr 139: 495-501.
- Jayasooriya AP, Begg DP, Chen N, Mathai ML, Sinclair AJ, et al. (2008) Omega-3 polyunsaturated fatty acid supplementation reduces hypertension in TGR(mRen-2)27 rats. Prostaglandins LeukotEssent Fatty Acids 78: 67-72.
- Owen RW, Giacosa A, Hull WE, Haubner R, Würtele G, et al. (2000) Olive-oil consumption and health: the possible role of antioxidants. Lancet Oncol 1: 107-112.
- Waterman E, Lockwood B (2007) Active components and clinical applications of olive oil. Altern Med Rev 12: 331-342.
- Terés S, Barceló-Coblijn G, Benet M, Alvarez R, Bressani R, et al. (2008) Oleic acid content is responsible for the reduction in blood pressure induced by olive oil. ProcNatlAcadSci U S A 105: 13811-13816.
- Samieri C, Féart C, Proust-Lima C, Peuchant E, Tzourio C, et al. (2011) Olive oil consumption, plasma oleic acid, and stroke incidence: the Three-City Study. Neurology 77: 418-425.
- Kris-Etherton PM, Harris WS, Appel LJ; Nutrition Committee (2003) Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. ArteriosclerThrombVascBiol 23: e20-30.
- Ottestad I, Hassani S, Borge GI, Kohler A, Vogt G, et al. (2012) Fish oil supplementation alters the plasma lipidomic profile and increases long-chain PUFAs of phospholipids and triglycerides in healthy subjects. PLoS One 7: e42550.
- Erkkilä AT, Schwab US2, Lehto S3, de Mello VD4, Kangas AJ5, et al. (2014) Effect of fatty and lean fish intake on lipoprotein subclasses in subjects with coronary heart disease: a controlled trial. J ClinLipidol 8: 126-133.
- Simão AN, Lozovoy MA, Dichi I (2014) Effect of soy product kinako and fish oil on serum lipids and glucose metabolism in women with metabolic syndrome. Nutrition 30: 112-115.
- Thompson PD, Buchner D, Pina IL, Balady GJ, Williams MA, et al. (2003) Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity). Circulation 107: 3109-3116.
- Meyer SB, Coveney J, Ward PR (2014) A qualitative study of CVD management and dietary changes: problems of 'too much' and 'contradictory' information. BMC FamPract 15: 25.
- Papanikolaou Y, Brooks J, Reider C, Fulgoni VL 3rd (2014) U.S. adults are not meeting recommended levels for fish and omega-3 fatty acid intake: results of an analysis using observational data from NHANES 2003-2008. Nutr J 13: 31.
- Carrillo C, CaviaMdel M, Alonso-Torre S (2012) Role of oleic acid in immune system; mechanism of action; a review. NutrHosp 27: 978-990.
- Obici S, Feng Z, Morgan K, Stein D, Karkanias G, et al. (2002) Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51: 271-275.
- Vassiliou EK, Gonzalez A, Garcia C, Tadros JH, Chakraborty G, et al. (2009) Oleic acid and peanut oil high in oleic acid reverse the inhibitory effect of insulin production of the inflammatory cytokine TNF-alpha both in vitro and in vivo systems. Lipids Health Dis 8: 25.
- Camell C, Smith CW (2013) Dietary oleic acid increases m2 macrophages in the mesenteric adipose tissue. PLoS One 8: e75147.
- Chung S, Yoon HE, Kim SJ, Kim SJ, Koh ES, et al. (2014) Oleanolic acid attenuates renal fibrosis in mice with unilateral ureteral obstruction via facilitating nuclear translocation of Nrf2. NutrMetab (Lond) 11: 2.
- Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, et al. (2006) Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review. BMJ 332: 752-760.
- Hennebelle M, Balasse L, Latour A, Champeil-Potokar G, Denis S, et al. (2012) Influence of omega-3 fatty acid status on the way rats adapt to chronic restraint stress. PLoS One 7: e42142.
- Stegemann C, Pechlaner R, Willeit P, Langley SR, Mangino M, et al. (2014) Lipidomics profiling and risk of cardiovascular disease in the prospective population-based Bruneck study. Circulation 129: 1821-1831.
- Subramaniam S, Fahy E, Gupta S, Sud M, Byrnes RW, et al. (2011) Bioinformatics and systems biology of the lipidome. Chem Rev 111: 6452-6490.