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Review
. 2018 Jan 4:11:43-55.
doi: 10.1016/j.jare.2018.01.002. eCollection 2018 May.

Arachidonic acid in health and disease with focus on hypertension and diabetes mellitus: A review

Undurti N Das  1   2
Affiliations
Review

Arachidonic acid in health and disease with focus on hypertension and diabetes mellitus: A review

Undurti N Das. J Adv Res. .

Abstract

Arachidonic acid (AA 20:4n-6) is an essential component of cell membranes and modulates cell membrane fluidity. AA is metabolized by cyclo-oxygenase (COX), lipoxygenase (LOX) and cytochrome P450 enzymes to form several metabolites that have important biological actions. Of all the actions, role of AA in the regulation of blood pressure and its ability to prevent both type 1 and type 2 diabetes mellitus seems to be interesting. Studies showed that AA and its metabolites especially, lipoxin A4 (LXA4) and epoxyeicosatrienoic acids (EETs), potent anti-inflammatory metabolites, have a crucial role in the pathobiology of hypertension and diabetes mellitus. AA, LXA4 and EETs regulate smooth muscle function and proliferation, voltage gated ion channels, cell membrane fluidity, membrane receptors, G-coupled receptors, PPARs, free radical generation, nitric oxide formation, inflammation, and immune responses that, in turn, participate in the regulation blood pressure and pathogenesis of diabetes mellitus. In this review, role of AA and its metabolites LXA4 and EETs in the pathobiology of hypertension, pre-eclampsia and diabetes mellitus are discussed. Based on several lines of evidences, it is proposed that a combination of aspirin and AA could be of benefit in the prevention and management of hypertension, pre-eclampsia and diabetes mellitus.

Keywords: Arachidonic acid; Cytokines; Diabetes mellitus; Free radicals; Hypertension; Inflammation; Lipoxin A4; Nitric oxide; Pre-eclampsia.

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Figures

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Graphical abstract
Fig. 1
Fig. 1
Scheme showing possible interaction(s) among various factors involved in the pathobiology of blood pressure maintenance and development of hypertension. (+) indicates enhancement of action/synthesis; (−) indicates decrease in synthesis/action. ASA = Aspirin. Aspirin is known to enhance the formation of LXA4, resolvins, protectins and maresins from their respective precursors. Legend to Fig. 1: High fat diet (HFD)/excess salt intake enhances pro-inflammatory cytokines IL-17, IL-6 and TNF-α production (by enhancing NF-kB expression) that may enhance ROS (reactive oxygen species) generation. ROS inactivates eNO production. HFD/excess salt intake also enhances ADMA formation that interferes with eNO production. IL-6 and TNF-α decrease activity of desaturases resulting in decreased conversion of dietary LA/ALA to AA/EPA/DHA, the precursors of LXA4/resolvins/protectins/maresins that enhance NO and decrease ROS generation and block IL-6, TNF-α and IL-17 formation and action. Thus, patients with HTN have low plasma NO, AA/EPA/DHA and LXA4/resolvins/protectins/maresins and higher concentrations of ADMA, ROS/lipid peroxides, IL-17/IL-6/TNF-α and decrease in the activity of Δ6 and Δ5 desaturases. Paradoxically, whenever there is deficiency of AA, production of PGE2 is increased (HFD/excess salt enhance COX-2 expression either directly or as a result of NF-kB activation), a pro-inflammatory molecule that can decrease IL-6 and TNF-α production as a feed-back regulatory evet but seldom is able to suppress inflammation , , , . Some studies suggested that under some very specific conditions, PGE2 may have anti-inflammatory actions and enhances tissue repair by augmenting the formation of LXA4 and 15-PGDH–deficient mice display a twofold increase in PGE2 levels across multiple tissues—including bone marrow, colon, and liver—and that they show increased fitness of these tissues in response to damage. Thus, PGE2 has many actions and may have both pro- and anti-inflammatory actions. Genetic polymorphisms of desaturases, COX-1 and COX-2 and 5-, 12-, 15-lipoxygenases (LOX) may also lead to decreased formation of AA/EPA/DHA/LXA4/resolvins/protectins/maresins and modulate development of HTN. Co-factors needed for optimal activity of desaturases and elongases are important for adequate formation of AA/EPA/DHA and hence, their deficiency may also have a role in the pathogenesis of HTN. Salt intake may also reduce the production of EETs that have vasodilator and anti-hypertensive function. EETs are derived from AA by the action of cytochrome P450 enzymes (soluble epoxide hydrolase). It is possible that EETs may interact with lipoxins. Resolvins, protectins, maresins.
Fig. 2
Fig. 2
Scheme showing interaction among high and low doses of IL-2/TNF-α in the induction and prevention of type 1 DM. It is likely that high doses of IL-2/TNF-α induce the activation of iPLA2 and COX-2 leading to the synthesis and release of excess of PGE2 and LTB4 and other pro-inflammatory molecules that, in turn, enhance ROS generation leading to apoptosis of pancreatic β cells and onset of type 1 DM. In contrast, low doses of IL-2/TNF-α activate sPLA2 and cPLA2 (cPLA2 > sPLA2) that leads to the synthesis and release of lipoxins, reoslvins, protectins and maresins which suppress the formation of ROS and enhance antioxidant Dasstatus of pancreatic β cells and prevention of type 1 DM. Same set of events are likely to occur in type 2 DM as well except that in this instance, IL-2/IL-6 and TNF-α produce sysemic insulin resistance. Production of adeuate amounts of lipoxins, resolvins, protectins and maresins suppress IL2/IL-6/TNF-α production and amelioration from systemic insulin resistance and type 2 DM. It is likely that activation of iPLA2 inhibit the formation of tolerogenic Dcs and enhance the occurrence of type 1 DM, whereas activation of cPLA2 enhances the formation of tolerogenic DCs and suppresses the occurrence of type 1 DM. It is alsopossible that activation of iPLA2 enhances the formation of pro-inflammmatory eicosanoids such as PGE2 and LTs, whereas activation of cPLA2 augments the formation of anti-inflammmatory lipoxins, resolvins, protectins and maresins. This figure is modified from Das UN. Frontiers Endocrinology 2017; 8:182 (Ref. [82]).
Fig. 3
Fig. 3
Scheme showing metabolism of arachidonic acid.
See this image and copyright information in PMC

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