nutrients Review A Novel Anti-Inflammatory Role of Omega-3 PUFAs in Prevention and Treatment of Atherosclerosis and Vascular Cognitive Impairment and Dementia 1, 2,3, 1 1 Marialaura Simonetto y, Marco Infante y , Ralph L. Sacco , Tatjana Rundek and David Della-Morte 1,3,4,* 1 Department of Neurology and The Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA; [email protected] (M.S.); [email protected] (R.L.S.); [email protected] (T.R.) 2 Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA; [email protected] 3 Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy 4 San Raffaele Roma Open University, 00166 Rome, Italy * Correspondence: [email protected] These authors contributed equally to this work. y Received: 24 July 2019; Accepted: 19 September 2019; Published: 23 September 2019 Abstract: Atherosclerosis is an inflammatory chronic disease affecting arterial vessels and leading to vascular diseases, such as stroke and myocardial infarction. The relationship between atherosclerosis and risk of neurodegeneration has been established, in particular with vascular cognitive impairment and dementia (VCID). Systemic atherosclerosis increases the risk of VCID by inducing cerebral infarction, or through systemic or local inflammatory factors that underlie both atherosclerosis and cognition. Omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) are involved in inflammatory processes, but with opposite roles. Specifically, omega-3 PUFAs exert anti-inflammatory properties by competing with omega-6 PUFAs and displacing arachidonic acid in membrane phospholipids, decreasing the production of pro-inflammatory eicosanoids. Experimental studies and some clinical trials have demonstrated that omega-3 PUFA supplementation may reduce the risk of different phenotypes of atherosclerosis and cardiovascular disease. This review describes the link between atherosclerosis, VCID and inflammation, as well as how omega-3 PUFA supplementation may be useful to prevent and treat inflammatory-related diseases. Keywords: omega-3 PUFAs; omega-6 PUFAs; inflammation; resolvins; AA/EPA ratio; atherosclerosis; cardiovascular risk; neurodegeneration; vascular cognitive impairment and dementia 1. Introduction to Omega-3 and Omega-6 PUFAs: An Overview of Their Metabolic Pathways Polyunsaturated fatty acids (PUFAs) are fatty acids with two or more double bonds in their carbon chain. PUFAs can be further categorized according to the location of the first double bond relative to the terminal methyl group: omega-3 and omega-6 PUFAs are characterized by the presence of a double bond three and six atoms away from the methyl terminus, respectively. Omega-3 and omega-6 PUFAs represent the most biologically significant PUFAs and their role in cardiovascular, inflammatory, and metabolic diseases has been extensively studied [1–4]. Figure1 illustrates the omega-6 and omega-3 PUFA biosynthetic pathway, which has already been extensively reviewed elsewhere [4,5]. Long-chain omega-3 and omega-6 PUFAs derive from alpha-linolenic acid (ALA, 18:3 !-3) and linoleic acid (LA, 18:2 !-6), respectively. ALA and LA are called essential fatty acids (EFAs), since mammals cannot synthetize them due to the lack of delta-12 Nutrients 2019, 11, 2279; doi:10.3390/nu11102279 www.mdpi.com/journal/nutrients Nutrients 2019, 11, 2279 2 of 28 Nutrients 2019, 11, x FOR PEER 2 of 29 and anddelta delta-15-15 desaturases, desaturases, which which are enzymes are enzymes only only present present in marine in marine algae algae and andplants plants [6]. [Humans6]. Humans mustmust therefore therefore obtain obtain EFAs EFAs through through dietarydietary sources. sources. The The main main dietary dietary sources sources of ALA of areALA represented are representedby dairy by products, dairy products and various, and seedsvarious and seeds seed and oils seed (especially oils (especially flaxseeds flaxseeds and walnut and oil), walnut whereas oil), corn, whereassaffl ower,corn, andsafflower sunflower, and oils sunflower are particularly oils are rich particul in LA.arly Humans rich in are LA. able H toumans metabolize are able ALA to and metabolizesynthesize ALA di andfferent synthesize downstream different very downstream long-chain andvery more long- unsaturatedchain and more omega-3 unsaturated PUFAs omega - including- 3 PUFAseicosapentaenoic - including eicosapentaenoic acid (EPA, 20:5 ! acid-3), docosapentaenoic (EPA, 20:5 ω-3), docosapentaenoic acid (DPA, 22:5 ! acid-3) and (DPA, docosahexaenoic 22:5 ω-3) and aciddocosahexaenoic (DHA, 22:6 ! acid-3) - through(DHA, 22:6 multiple ω-3) - enzymatic through multiple elongation enzymatic and desaturation elongation reactions, and desaturation which mainly reactionsoccur, which in the mainly liver (Figure occur 1in)[ the5,7 liver]. However, (Figure 1) very [5,7] long-chain. However, omega-3very long PUFAs-chain omega can be-3 also PUFAs directly can beobtained also directly through obtained different through dietary different sources (coddietary liver sources oil, oily (cod fish, liver algal oil, oils) oily [ 5fish,]. The algal omega-6 oils) [5 PUFA]. The arachidonicomega-6 PUFA acid arachidonic (AA, 20:4 ! acid-6) (AA, can either 20:4 ω be-6) obtained can either from be obtained some dietary from some sources dietary (especially sources meat, (especiallyegg yolk meat, and dairyegg yolk products) and dairy or be products) synthesized or endogenouslybe synthesized from endogenously the omega-6 from precursor the omega LA through-6 precursora series LA of through enzymatic a series elongation of enzymatic and desaturation elongation and reactions desaturation (Figure reactions1)[ 4,8]. Delta-5(Figure 1) and [4, delta-68]. Deltadesaturases-5 and delta (encoded-6 desaturases by FADS1 (encodedand FADS2by FADS1genes, and respectively) FADS2 genes, are respectively) the rate-limiting are the enzymes rate- for limitingPUFA enzymes metabolism, for PUFA and thus,metabolism, the main and determinants thus, the main of PUFA determinants levels [9 ].of PUFA levels [9]. FigureFigure 1. Metabolism 1. Metabolism of omega of omega-3-3 and omega and omega-6-6 PUFAs. PUFAs. Abbreviations: Abbreviations: FADS, FADS, Fatty Fatty acid aciddesaturase; desaturase; PUFAs,PUFAs, polyunsaturate polyunsaturatedd fatty fattyacids. acids. 2. Role2. Role of omega of Omega-3-3 and omega and Omega-6-6 PUFAs PUFAs in systemic in Systemic inflammation Inflammation LipidLipid mediators mediators deriv deriveded from from the omega the omega-6-6 PUFA PUFA AA are AA involved are involved in inflammation in inflammation at different at different stages.stages. In particular, In particular, the i thenitiation initiation of acute of acute inflammation inflammation is regulated is regulated by several by several lipid lipid mediators, mediators, includingincluding the theeicosanoids eicosanoids prostaglandins prostaglandins (PGs), (PGs), thromboxane thromboxaness (TXs) (TXs) and and leukotrienes leukotrienes (LTs) (LTs),, whichwhich play playa a pivotal pivotal role role in in the the modulation modulation of blood of blood flood, flood, endothelial endothelial permeability, permeability polymorphonuclear, polymorphonuclear neutrophil neutrophil(PMN) chemotaxis,(PMN) chemotaxis and platelet, and aggregation platelet aggreg [10,11ation]. Cyclooxygenase [10,11]. Cyclooxygenase (COX) and lipoxygenase (COX) and (LO) lipoxygenaseenzymes catalyze(LO) enzymes the conversion catalyze of the AA conversion into a series of of AA pro-inflammatory into a series mediators,of pro-inflammatory includingPGs, mediators,prostacyclin including (PGI2), PGs, TXA2 prostacyclin and pro-inflammatory (PGI2), TXA2 and leukotrienes, pro-inflammatory which leukotrienes are also known, which as 4-seriesare also leukotrienesknown as 4-series (Figure leukot2)[12rienes,13]. (Figure 2) [12,13]. Nutrients 2019, 11, 2279 3 of 28 Nutrients 2019, 11, x FOR PEER 3 of 29 Figure 2. Eicosanoid and specialized pro-resolving mediator biosynthesis. The omega-6 PUFA arachidonicFigure 2. Eicosanoid acid is the precursor and specialized of the pro-inflammatory pro-resolving eicosanoids.mediator biosynthesis. Cyclooxygenase The and omega lipoxygenase-6 PUFA enzymesarachidonic catalyze acid theis the conversion precursor of arachidonicof the pro- acidinflammatory into a series eicosanoids. of pro-inflammatory Cyclooxygenase mediators, and includinglipoxygenase prostaglandins, enzymes catalyze thromboxanes the conversion and pro-inflammatory of arachidonic acid leukotrienes into a series (4-series of pro- leukotrienes).inflammatory Themediators, omega-3 including PUFA eicosapentaenoic prostaglandins,acid thromboxanes is also a substrate and pro for-inflammatory arachidonic acid-cascadeleukotrienes enzymes(4-series (cyclooxygenaseleukotrienes). The and omega 5-lipoxygenase),-3 PUFA eicosapentaenoic leading to the production acid is also of alternative a substrate omega-3 for arachidonic PUFA-derived acid- eicosanoids,cascade enzym suches as(cyclooxygenase 3-series prostanoids and and5-lipoxygenase 5-series leukotrienes,), leading whichto the areproduction inactive metabolitesof alternative or displayomega- lower3 PUFA pro-inflammatory-derived eicosanoids, activity such compared as 3-series to arachidonicprostanoids acid-derivedand 5-series leukotrienes, eicosanoids. Moreover,which are omega-3inactive PUFAsmetabolites represent or thedisplay precursors lower of pro a series-inflammatory