A Novel Anti-Inflammatory Role of Omega-3 PUFAs in Prevention and Treatment of Atherosclerosis and Vascular Cognitive Impairment and Dementia

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: AA/EPA ratio; atherosclerosis; cardiovascular risk; inflammation; neurodegeneration; omega-3 PUFAs; omega-6 PUFAs; resolvins; vascular cognitive impairment and dementia.

Figure 1

Metabolism of omega-3 and omega-6 PUFAs. Abbreviations: FADS, Fatty acid desaturase; PUFAs, polyunsaturated fatty acids.

Figure 2

Eicosanoid and specialized pro-resolving mediator biosynthesis. The omega-6 PUFA arachidonic acid is the precursor of the pro-inflammatory eicosanoids. Cyclooxygenase and lipoxygenase enzymes catalyze the conversion of arachidonic acid into a series of pro-inflammatory mediators, including prostaglandins, thromboxanes and pro-inflammatory leukotrienes (4-series leukotrienes). The omega-3 PUFA eicosapentaenoic acid is also a substrate for arachidonic acid-cascade enzymes (cyclooxygenase and 5-lipoxygenase), leading to the production of alternative omega-3 PUFA-derived eicosanoids, such as 3-series prostanoids and 5-series leukotrienes, which are inactive metabolites or display lower pro-inflammatory activity compared to arachidonic acid-derived eicosanoids. Moreover, omega-3 PUFAs represent the precursors of a series of lipid mediators, including resolvins, protectins and maresins, which are collectively termed “specialized pro-resolving mediators” (SPMs). Abbreviations: 5-HPETE, 5-hydroperoxyeicosatetraenoic acid; 5-LO, 5-lipoxygenase; AA, arachidonic acid; COX-1, cyclooxygenase-1; COX-2, cyclooxygenase-2; Cyt P450, cytochrome P450; EPA, eicosapentaenoic acid; LO, lipoxygenase; LTA4, leukotriene A4; LTB4, leukotriene B4; LTB5, leukotriene B5; LTC4, leukotriene C4; LTC5, leukotriene C5; LTD4, leukotriene D4; LTD5, leukotriene D5; LTE4, leukotriene E4; LTE5, leukotriene E5; MaR1, maresin 1; NPD1, neuroprotectin D1; PD1, protectin D1; PGD2, prostaglandin D2; PGE2, prostaglandin E2; PGE3, prostaglandin E3; PGF2, prostaglandin F2; PGH2, prostaglandin H2; PGI2, prostacyclin; PUFA, polyunsaturated fatty acid; RvD1, resolvin D1; RvD2, resolvin D2; RvD3, resolvin D3; RvD4; resolvin D4; RvE1, resolvin E1; RvE2, resolvin E2; RvE3, resolvin E3; SPMs, specialized pro-resolving mediators; TXA2, thromboxane A2; TXA3, thromboxane A3.

Figure 3

Potential mechanisms underlying the protective effects of omega-3 PUFAs EPA and DHA against vascular inflammation and atherosclerosis. Abbreviations: 18-HEPE, 18-monohydroxy EPA; ADP, adenosine diphosphate; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; IL-6, interleukin-6; LDL, low-density lipoprotein; LTB4, leukotriene B4; RvE1, resolvin E1; RvD1, resolvin D1; SPMs, specialized pro-resolving mediators; TXA2, thromboxane A2; VSMCs, vascular smooth muscle cells.