Omega‐3 polyunsaturated fatty acids and hypertension: a review of vasodilatory mechanisms of docosahexaenoic acid and eicosapentaenoic acid

Abstract

Hypertension is often characterised by impaired vasodilation involving dysfunction of multiple vasodilatory mechanisms. ω‐3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) can reduce blood pressure and vasodilation. In the endothelium, DHA and EPA improve function including increased NO bioavailability. However, animal studies show that DHA‐ and EPA‐mediated vasodilation persists after endothelial removal, indicating a role for vascular smooth muscle cells (VSMCs). The vasodilatory effects of ω‐3 PUFAs on VSMCs are mediated via opening of large conductance calcium‐activated potassium channels (BKCa), ATP‐sensitive potassium channels (KATP) and possibly members of the Kv7 family of voltage‐activated potassium channels, resulting in hyperpolarisation and relaxation. ω‐3 PUFA actions on BKCa and voltage‐gated ion channels involve electrostatic interactions that are dependent on the polyunsaturated acyl tail, cis‐geometry of these double bonds and negative charge of the carboxyl headgroup. This suggests structural manipulation of ω‐3 PUFA could generate novel, targeted, therapeutic leads.

Subtype specific responses in hKv7.4 and hKv7.5 channels to polyunsaturated fatty acids

“…Increased consumption of foods rich in PUFAs have long been associated with improved cardiovascular health (Bang et al, 1980, Kagawa et al, 1982, Saravanan et al, 2010 and multiple mechanisms have been proposed including those mediated by the immune system, the endothelium and vascular smooth muscle tissues (Massaro et al, 2008). Several ion channels have been studied as the molecular correlates of PUFA-mediated vasodilatory mechanisms in both endothelial cells and VSMCs (Bercea et al, 2021). Among others, PUFA induced inhibition of L-type CaV channels (Engler et al, 2000) and PUFA induced activation of large conductance Ca 2+activated K + (BK) channels contribute to the vasodilation induced by PUFA (Hoshi et al, 2013, Limbu et al, 2018.…”

“…For instance, the protective PUFA effect on hearing loss has been attributed to cerebrovascular effects, reasoning that PUFAs improve circulation to the cochlea (Dullemeijer et al, 2010, Gopinath et al, 2010, Curhan et al, 2014. PUFA-induced vasodilation has in part been attributed to the activation of Ca 2+ -dependent and ATP sensitive K + channels by PUFAs (Hoshi et al, 2013, Limbu et al, 2018, Bercea et al, 2021. However, little is known about the putative contribution of KV7.4 and KV7.5 channels to PUFA effects.…”

“…KV7.5 is more widely spread through the central nervous system and is particularly important in regulating excitability in the hippocampus (Schroeder et al, 2000, Tzingounis et al, 2010, Fidzinski et al, 2015. KV7.1, KV7.4 and KV7.5 are expressed in various smooth muscle cells such as vascular smooth muscle cells (VSMC), suggesting that several KV7 subtypes, including heterotetrameric KV7.4/7.5 channels, may contribute to the hyperpolarizing K + current in VSMCs that promotes vasodilation by preventing Ca 2+ -dependent contraction (Ng et al, 2011, Mani et al, 2013, Stott et al, 2014, Bercea et al, 2021, The modulation of KV7.1 and KV7.2/7.3 channels by endogenous and pharmacological compounds has been extensively studied (Miceli et al, 2018, Wu and. However, less is known about the modulation of KV7.4 and KV7.5.…”

Eicosanoid profiling in patients with complete form of pachydermoperiostosis carrying SLCO2A1 mutations

“…EPA and DHA are essential fatty acids belonging to the ω-3 polyunsaturated fatty acid (PUFA) group, which has an anti-inflammatory role. 14 13HODE and AA are ω-6 PUFA, which promote inflammation. 14 The pro-inflammatory state of PDP patients may reduce the production of ω-6 PUFA through an unidentified negative feedback mechanism.…”

“…14 13HODE and AA are ω-6 PUFA, which promote inflammation. 14 The pro-inflammatory state of PDP patients may reduce the production of ω-6 PUFA through an unidentified negative feedback mechanism.…”