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. Author manuscript; available in PMC: 2024 Mar 7.
Published in final edited form as: Adv Pharmacol. 2023 May 10;97:1–35. doi: 10.1016/bs.apha.2023.01.001

Bioactive lipids in hypertension

John D Imig 1,*
PMCID: PMC10918458  NIHMSID: NIHMS1966750  PMID: 37236756

Abstract

Hypertension is a major healthcare issue that afflicts one in every three adults worldwide and contributes to cardiovascular diseases, morbidity and mortality. Bioactive lipids contribute importantly to blood pressure regulation via actions on the vasculature, kidney, and inflammation. Vascular actions of bioactive lipids include blood pressure lowering vasodilation and blood pressure elevating vasoconstriction. Increased renin release by bioactive lipids in the kidney is pro-hypertensive whereas anti-hypertensive bioactive lipid actions result in increased sodium excretion. Bioactive lipids have pro-inflammatory and anti-inflammatory actions that increase or decrease reactive oxygen species and impact vascular and kidney function in hypertension. Human studies provide evidence that fatty acid metabolism and bioactive lipids contribute to sodium and blood pressure regulation in hypertension. Genetic changes identified in humans that impact arachidonic acid metabolism have been associated with hypertension. Arachidonic acid cyclooxygenase, lipoxygenase and cytochrome P450 metabolites have pro-hypertensive and anti-hypertensive actions. Omega-3 fish oil fatty acids eicosapentaenoic acid and docosahexaenoic acid are known to be anti-hypertensive and cardiovascular protective. Lastly, emerging fatty acid research areas include blood pressure regulation by isolevuglandins, nitrated fatty acids, and short chain fatty acids. Taken together, bioactive lipids are key contributors to blood pressure regulation and hypertension and their manipulation could decrease cardiovascular disease and associated morbidity and mortality.

1. Introduction

Hypertension is defined as a blood pressure that is consistently above 130/80 mmHg. Recent Centers for Disease Control and Prevention statistics found that over 30% of adults in the United States have hypertension (Saglietto et al., 2021; Townsend et al., 2021). Chronic hypertension is a major contributor to cardiovascular, kidney, and cerebral disease morbidity and mortality (Francula-Zaninovic & Nola, 2018). When combined with other diseases such as metabolic syndrome and diabetes, the long-term consequences of hypertension significantly impact quality of life (Francula-Zaninovic & Nola, 2018; Saglietto et al., 2021). There have been great advances in the management and treatment of hypertension; however, the prevalence of uncontrolled hypertension remains at 50% (Egan & Laken, 2011). Consequently, identifying new approaches for the management and treatment of hypertension are needed.

Management for hypertension has focused on lifestyle changes such as exercise, weight loss, decreased salt consumption, and decreasing daily stress. Treatment of hypertension has been aimed at the primary contributors to blood pressure control. These include the renin-angiotensin-aldosterone system, vascular smooth muscle, kidney sodium transport, and β adrenergic system (Khan & Imig, 2018). Unfortunately, the complex and interacting mechanisms that result in an elevated blood pressure and chronic hypertension make for difficult management and treatment options. Genetic factors, environmental factors, and socio-economic factors also complicates the management and treatment of hypertension.

If new hypertension management and treatments are to emerge, then we need to find ways to combat the complex and interacting mechanisms responsible for elevating blood pressure. Interacting mechanisms that elevate blood pressure include inflammation, endothelial dysfunction, and improper renal and water and electrolyte regulation (Khan & Imig, 2018). Intriguingly, fatty acids and fatty acid metabolites provide opportunities to both manage and treat hypertension. For example, it is widely recognized that a fish oil diet high in omega-3 fatty acids results in decreased cardiovascular disease and related mortality (Colussi, Catena, Novello, Bertin, & Sechi, 2017; Shramko, Polonskaya, Kashtanova, Stakhneva, & Ragino, 2020). This reduced cardiovascular disease has been attributed to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and their metabolites (Colussi et al., 2017). Likewise, an imbalance of cyclooxygenase (COX), lipoxygenase (LO), and cytochrome P450 (CYP) metabolites of arachidonic acid (AA) results in hypertension (Khan, Xiao, & Cheang, 2021; Shramko et al., 2020). The fatty acids arachidonic acid, EPA, and DHA and their metabolites can impact inflammation, endothelial and vascular smooth muscle function, and kidney water and electrolyte regulation (Colussi et al., 2017; Zhao, Hasse, & Bourgoin, 2021). There has been significant progress over the past decade to evaluate these bioactive lipids to manage and treat hypertension and associated metabolic, renal, and cardiovascular diseases.

2. Bioactive lipid pathways and metabolites

Fatty acids are an essential dietary component and are abundant in cell membranes where they can be released by the actions of phospholipase enzymes (Fig. 1). Phospholipase A2 is responsible for the release of polyunsaturated fatty acids from the sn-2 position of the cell membrane phospholipids (Zhao et al., 2021). The omega-6 arachidonic acid is an essential fatty acid that when liberated from cell membranes can be acted upon by series of enzymes resulting in bioactive lipids (Imig, 2020). Omega-3 fatty acids EPA and DHA become more abundant in cell membranes in populations that consume diets high in fish oils or take over the counter fish oil supplements (Colussi et al., 2017). Like arachidonic acid, EPA and DHA are released from cell membranes and converted to bioactive lipids (Schunck, Konkel, Fischer, & Weylandt, 2018). Bioactive COX, LO, and CYP lipid metabolites of arachidonic acid, EPA, and DHA can impact kidney, inflammatory, and cardiovascular function (Colussi et al., 2017; Schunck et al., 2018).

Fig. 1.

Fig. 1

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Bioactive lipids that contribute to blood pressure regulation and hypertension: Fatty acids are converted to metabolites by enzymes. Fatty acid metabolites then act on receptors or independent of receptors to have vascular, kidney, and inflammatory actions that are pro-hypertensive or anti-hypertensive.

The COX pathway has been the most extensively studied of the three fatty acid metabolic pathways. COX enzymes are widely expressed in kidney and cardiovascular structures (Cheng & Harris, 2004; Das, 2018; Imig, 2006). There are two COX isoforms, COX-1 and COX-2 that convert arachidonic acid into prostaglandin H2 (PGH2). PGH2 is then converted by synthases into thromboxane (TX) and bioactive PGs. TX, PGI2, PGF2α, PGE2, and PGD2 then act on receptors in the kidney, endothelium, and vascular smooth muscle cells to effect inflammation, water and electrolyte regulation and vascular resistance (Cheng & Harris, 2004; Imig, 2006). These COX metabolites can have antihypertensive or prohypertensive properties depending on the profile of prostanoids produced and receptor expression (Cheng & Harris, 2004; Matsumoto, Goulopoulou, Taguchi, Tostes, & Kobayashi, 2015; Yuhki et al., 2011). The impact of COX metabolites on hypertension has been highlighted by the findings that COX inhibitors can elevate blood pressure and antagonize the effects of antihypertensive medications (Grosser, Ricciotti, & FitzGerald, 2017).

LO enzymes generate leukotrienes (LTs), hydroxyeicosatraenoic acids (HETEs) and lipoxins (LXs). Expression of LO enzymes are localized to platelets, neutrophils, and macrophages (Dobrian, Cole, Chakrabarti, et al., 2011; Singh & Rao, 2019). Once generated, LO metabolites act on receptors to exert effects on renal and cardiovascular function (Dobrian et al., 2011; Imig & Khan, 2015). Inflammatory actions described for LO metabolites can also impact blood pressure regulation (Singh & Rao, 2019). LO metabolites increase oxidative stress and vascular reactivity which contribute to hypertension and associated cardiovascular diseases (Imig, 2020).

The third pathway is the CYP enzymatic pathway that generates epoxyeiocsatrienoic acids (EETs) and HETEs. CYP enzymes include the omega-hydroxylase CYP4As generating HETEs and the epoxygenase CYP2C and CYP2J enzymes generating EETs (Capdevila, Falck, & Imig, 2007). These CYP enzymes are expressed in renal and cardiovascular structures (Imig, 2006; Imig & Khan, 2015). EETs have been demonstrated to be antihypertensive whereas 20-HETE has been demonstrated to be primarily hypertensive (Fan & Roman, 2017). Pharmacological manipulation of CYP enzymatic pathways and EETs and 20-HETE have been developed to combat hypertension and cardiovascular diseases (Fan & Roman, 2017; Imig, 2018).

Although arachidonic acid is the most abundant fatty acid in cell membranes and arachidonic acid metabolites represent the major metabolites, EPA and DHA metabolites are generated by COX, LO, and CYP pathways (Schunck et al., 2018). The COX, LO, and CYP metabolites of EPA and DHA have beneficial actions to oppose hypertension and cardiovascular diseases (Colussi et al., 2017; Schunck et al., 2018). Lastly, emerging areas of bioactive lipids in hypertension include isolevuglandins (IsoLGs), nitrated fatty acids, and short chain fatty acids (SCFAs). Reactive oxygen species result in arachidonic acid peroxidation leading to IsoLGs (Davies et al., 2020). This activation occurs at the immune cell activation where the formation of IsoLGs and inflammatory activity elevate blood pressure and cause end organ damage (Elijovich, Kleyman, Laffer, & Kirabo, 2021). SCFAs are fatty acids with fewer than six carbons. The primary SCFAs produced by the gut microbiota are butyrate and propionate which act on G-protein coupled receptors (GPCRs) to influence blood pressure regulation (Chen, Chen, & Tang, 2020; Xu, Moore, & Pluznick, 2022). Likewise, nitro-fatty acids are endogenously formed by the reaction of reactive nitrogen species with unsaturated fatty acids (Mollenhauer, Mehrkens, & Rudolph, 2018). The covalent binding of nitro-fatty acids to cysteine residues and post-translational protein modifications can act as potent anti-inflammatory signaling mediators (Villacorta, Gao, Schopfer, Freeman, & Chen, 2016). Nitro-fatty acids activate peroxisome proliferator-activated receptor γ (PPARγ) and inhibit nuclear factor-kappa β (NF-κβ) to reduce inflammation (Mollenhauer et al., 2018). These findings have led to targeting EPA, DHA, IsoLGs, SCFAs, and nitro-fatty acids to treat inflammation and cardiovascular diseases.

3. Human genetic studies implicating bioactive lipids in hypertension

Human genetics has provided insight into bioactive lipids in hypertension. There is limited information of COX and LO pathway and their receptors in regard to human genetics and blood pressure regulation. Although there is limited information on COX and LO genetic changes in hypertension, human genetic variants have been associated with inflammatory diseases, atherosclerosis, ischemic disease, and platelet function (Grosser et al., 2017). Interestingly, LO genetic variants have been linked to pulmonary arterial hypertension (Dobrian et al., 2011; Singh & Rao, 2019). Human genetic variants in the CYP pathway have been associated with hypertension (Bellien & Joannides, 2013). CYP genetic variants regulate key enzymes resulting in changes in pro- or anti-hypertensive CYP metabolites (Bellien & Joannides, 2013). Likewise, variants in fatty acid desaturase (FADS) genes that regulate conversion of omega-3 and omega-6 fatty acids can predispose individuals to metabolic and cardiovascular diseases (Panda, Varadharaj, & Voruganti, 2022).

Although limited, COX pathway genetic variants have been associated with hypertension. Three single-nucleotide polymorphisms (SNP) in the human prostaglandin E2 receptor EP2 (PTGER2) identified SNP rs17197 as being associated with essential hypertension in Japanese males (Sato et al., 2007). Likewise, mutations of the human prostacyclin synthase gene are associated with essential hypertension (Nakayama, 2005). A rare SNP that allows for increased expression of the PGF2α receptor associated with the risk of essential hypertension in the Han Chinese population (Xiao et al., 2015). Likewise, human genetic variants in COX-2 (PTGS2) have been found to associate with hypertension and salt-sensitive blood pressure regulation. A large-scale epidemiological study found that a PTGS2 polymorphism associated with hypertension in the Japanese population (Wang, Sun, et al., 2020; Wang, Zhou, et al., 2020). Two PTGS2 SNPs rs689466 and rs12042763 were also determined to associate with blood pressure changes over time in a Chinese population (Wang, Sun, et al., 2020; Wang, Zhou, et al., 2020). Intriguingly, PTGS2 SNP rs12042763 demonstrated a positive association with the systolic blood pressure response to low salt dietary intake (Wang, Sun, et al., 2020; Wang, Zhou, et al., 2020). These genetic variants in the COX-2, PGF2α receptor, and PGE2 EP2 receptor have key actions on kidney sodium transport and vascular reactivity actions that would impact blood pressure regulation.

CYP pathway human genetic variants that regulate EET levels have been demonstrated to associate with hypertension (Bellien & Joannides, 2013). Genetic variants in CYP2C8, CYP2C9, and CYP2J2 result in reduced levels of the anti-hypertensive EETs (Bellien & Joannides, 2013; Spiecker et al., 2004). The CYP2J*7 allele results in decreased EET levels and associates with essential hypertension in a Russian cohort (Polonikov et al., 2017). Other human studies have failed to demonstrate that the CYP2J*7 allele is associated with hypertension (King et al., 2005). Although human studies have found that CYP2C genetic variants do not associate with hypertension in Caucasian and African American cohorts, the frequency of the CYP2C9*3 allele was found to be lower in Asian females with hypertension (Yu et al., 2004). Human genetic studies have also evaluated soluble epoxide hydrolase (sEH) that converts active EETs to less active diols. Polymorphisms in the sEH gene, EPHX2, have not been found to associate with hypertension (Imig, Jankiewicz, & Khan, 2020). On the other hand, EPHX2 genetic variants have been found to associate with blood flow responses and endothelial function (Lee et al., 2011).

Genetic variants in CYP enzymes that regulate 20-HETE levels have been associated with cardiovascular diseases including hypertension. CYP4A11 allele 8590C was found to associate with hypertension in Caucasian in Tennessee, in the Framingham population, in Germans, and in Swedes (Gainer et al., 2005; Williams, Hopkins, Jeunemaitre, & Brown, 2011). This CYP4A11 allele did not associate with hypertension in a case control study in an Australian population (Ward et al., 2008). Interestingly, polymorphisms in the CYP4A11 gene reduce enzymatic activity and decrease urinary 20-HETE levels (Gainer et al., 2005; Williams et al., 2011). The decrease in urinary 20-HETE levels in humans with CYP4A11 polymorphisms associates with salt-sensitive hypertension (Laffler et al., 2014; Williams et al., 2011). This finding supports a role for CYP4A11 in renal tubular transport regulation of electrolyte homeostasis and blood pressure regulation (Fan & Roman, 2017). The CYP4F2 V433M allele has been demonstrated to associate with elevated urinary 20-HETE levels suggesting a vascular pro-hypertensive effect (Stec, Roman, Flasch, & Rieder, 2007). Associations of the CYP4F2 V433M allele with hypertension have been demonstrated in Indian and Australians (Geng, Li, Wang, & Wang, 2019; Luo, Li, & Li, 2015). In addition, a CYP4F2 construct haplotype was associated with increased 20-HETE urinary excretion and hypertension in a Chinese population (Liu et al., 2008).

Regulation of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) by human genetic variants could also impact blood pressure regulation. FADS1 and FADS2 are considered the rate limiting enzymes for fatty acid metabolism (Panda et al., 2022). FADS haplotypes have been associated with an enhanced ability to produce arachidonic acid and EPA from their precursors (Panda et al., 2022). In addition, diets rich in omega-6 polyunsaturated fatty acids have efficient conversion of linoleic acid to arachidonic acid by the FADS haplotype D which genetically predisposes individuals to inflammatory metabolic diseases (Cribb et al., 2018; Simopoulos, 2021). Although the cardiovascular protective actions for omega-3 EPA and DHA are well described, the consequence of human genetic FADS variants on blood pressure control remains limited (Colussi et al., 2017; Panda et al., 2022). The common variant in the FADS1 gene, rs174546, associates with lower arachidonic acid levels and has a favorable association with blood pressure in European children (Wolters et al., 2017). These limited findings suggest that regulation of omega-3 and omega-6 PUFAs by FADS could impact blood pressure regulation and hypertension.

4. Bioactive lipids and vascular function in hypertension

Increased vascular resistance is a factor that leads to an elevated blood pressure and hypertension. Vascular resistance is controlled by the actions of the endothelial and vascular smooth muscle cells. Endothelial cells interact with circulating factors such as inflammatory cytokines. In response to circulating factors the endothelial cells generate nitric oxide, endothelin, prostaglandins, EETs, and 20-HETE that subsequently act on the vascular smooth muscle cell to regulate vascular resistance (Imig, 2020; Mitchell & Kirkby, 2019). Bioactive lipids can be circulating factors that interact at the endothelial cell, can be endothelial generated paracrine factors that influence vascular smooth muscle cells, or can be hormonal factors that act on vascular smooth muscle cell receptors (Imig, 2020; Mitchell & Kirkby, 2019). In hypertension, an imbalance in bioactive lipids results in endothelial dysfunction and enhanced vascular smooth muscle reactivity that contributes to increased vascular resistance and an elevated blood pressure (Fig. 2) (Imig, 2020; Matsumoto et al., 2015).

Fig. 2.

Fig. 2

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Vascular actions of bioactive lipids: Bioactive lipids can result in vasoconstriction to increase blood pressure or vasodilation to decrease blood pressure.

COX metabolites generated by arteries and arterioles can be antihypertensive or prohypertensive depending on the prevailing PGs produced (Matsumoto et al., 2015). Endothelial cells and to a lesser extent vascular smooth muscle cells generate COX metabolites (Matsumoto et al., 2015; Mitchell & Kirkby, 2019). COX-1 and COX-2 are expressed in endothelial cells and increase PG production in response to shear stress (Félétou, Huang, & Vanhoutte, 2010). PGs contribute to organ blood flow, vascular inflammation, and platelet aggregation (Mitchell & Kirkby, 2019). The impact for COX metabolites in hypertension has been extensively studied (Mitchell & Kirkby, 2019). In hypertension there is a shift in COX metabolites from vasodilation and antithrombosis to vasoconstriction, thrombosis, and inflammation (Matsumoto et al., 2015; Mitchell & Kirkby, 2019).

Hypertension animal models have provided extensive experimental evidence for dysregulation of vascular COX metabolites contributing to an elevated blood pressure (Matsumoto et al., 2015; Yuhki et al., 2011). PGE2 and actions on vascular EP receptors can impact blood pressure regulation (Yuhki et al., 2011). EP1 receptor knockout mice have decreased blood pressure and cardiovascular events in severe hypertension induced by uninephrectomy, deoxycorticosterone-acetate (DOCA), and angiotensin (Bartlett, Boyd, Harris, Zent, & Breyer, 2012; Nasrallah et al., 2020; Swan & Breyer, 2011). Likewise, the EP1 antagonist SC51322 reduces blood pressure in spontaneously hypertensive rats (SHR) (Guan et al., 2007). On the other hand, EP4 receptor activation reduces blood pressure in Dahl-salt sensitive rats (Xu et al., 2020). These findings demonstrate that PGE2 can have antihypertensive and prohypertensive actions depending on the EP receptor activated.

Endothelial contracting factors are elevated in spontaneously hypertensive rats (SHR) due to changes in COX metabolites (Félétou et al., 2010). Aortic COX-1, thromboxane synthase (TXS), and prostacyclin synthase (PGIS) expression are increased in SHR (Graham & Rush, 2009). These changes in SHR aorta result in a predominance of endothelial contracting factors (Félétou et al., 2010; Graham & Rush, 2009). In addition, COX-1 mediated endothelial contracting factors occur at an early age in SHR (Graham & Rush, 2009). There also is an inability of vasodilator PGs to buffer arteriolar vascular responses to angiotensin in SHR and angiotensin hypertension (Félétou et al., 2010; Imig, 2020). This enhanced vascular reactivity is likely the consequence of increased TX receptor (TP) sensitivity to PGI2 that results in endothelial-dependent vasoconstriction (Félétou et al., 2010). COX-1 endothelial cell generation of reactive oxygen species that decrease nitric oxide bioavailability also contributes to vasoconstriction in hypertension (Félétou et al., 2010). The endothelial-dependent vasoconstriction in hypertension can be reduced by COX-1 inhibition or COX-1 genetic deletion (Félétou et al., 2010; Yuhki et al., 2011). TP receptor deficient mice also have attenuated angiotensin hypertension that is in part due to decreased vascular resistance (Francois, Athirakul, Mao, Rockman, & Coffman, 2004). Elevations in endothelial cell COX-2 can generate vasoconstrictor metabolites in aorta and arterioles in SHR (Félétou et al., 2010; Imig, 2020). Likewise, humans with hypertension also have elevated COX-2 levels in renal arteries that can contribute to vascular dysregulation and increased vascular resistance (Wong et al., 2009). Taken together, these findings demonstrate that COX metabolites can contribute to endothelial and vascular dysregulation in hypertension.

LO metabolites can also contribute to increased vascular reactivity and resistance in hypertension. 12/15-LO is expressed in endothelial and vascular smooth muscle cells (Maayah & El-Kadi, 2016; Singh & Rao, 2019). Elevated LO enzyme activity and 12S-HETE levels have been determined in humans with essential hypertension and SHR (Kim, Jeong, Park, Lee, & Kim, 2013; Quintana, Guzmán, Collado, Clària, & Poch, 2006). Likewise, vascular 12-LO and 12S-HETE are increased in angiotensin hypertension (Anning et al., 2005; Nozawa et al., 1990). 12S-HETE constricts renal arterioles through activation of protein kinase C (PKC) and voltage-gated calcium channels (Yiu, Zhao, Inscho, & Imig, 2003). The aorta constrictor response to angiotensin in SHR is enhanced by 12S-HETE that increases vascular smooth muscle cell calcium signaling (Kim et al., 2013). In addition, LO metabolites can act to decrease vascular PGI2 levels which increases angiotensin reactivity in hypertension (Stanke-Labesque, Hardy, Cracowski, & Bessard, 2002; Takizawa, DelliPizzi, & Nasjletti, 1998). Mice deficient in 12/15-LO demonstrate increased vascular endothelial nitric oxide synthase (eNOS) and nitric oxide and lower blood pressure in angiotensin hypertension (Anning et al., 2005). More recent studies implicate macrophage produced 12S-HETE acting on the endothelial cell to produce an iso-thromboxane that acts on vascular smooth muscle cell TP receptors as contributing to increased vascular reactivity and resistance in hypertension (Kriska et al., 2022).

Vascular CYP metabolites have also been implicated in hypertension. 20-HETE acts on vascular smooth muscle cells to activate PKC and voltage-gated calcium channels resulting in vasoconstriction (Obara, Koide, & Nakayama, 2002; Sun, Falck, Harder, & Roman, 1999). On the other hand, EETs produced by endothelial cells activate vascular smooth muscle cell large-conductance K+ channels to cause vasodilation (Campbell et al., 2002; Imig, Dimitropoulou, Reddy, White, & Falck, 2008). Hypertension has been associated with increased vascular 20-HETE levels or decreased vascular EET levels (Fan & Roman, 2017; Imig, 2018). Elevated vascular sEH results in decreased EET levels which contributes to endothelial dysfunction and enhanced angiotensin vascular reactivity in SHR and angiotensin hypertension (Imig et al., 2005; Koeners et al., 2011; Zhao et al., 2004). Elevated 20-HETE levels contributes to vascular dysfunction in Dahl salt-sensitive hypertensive rats (Lukaszewicz & Lombard, 2013). Long-term CYP4A overexpression in rat results in elevated 20-HETE levels that cause endothelial dysfunction and hypertension (Agostinucci, Hutcheson, Hossain, Villegas, et al., 2022). This endothelial specific overexpression of CYP4A increases angiotensin converting enzyme and angiotensin type 1 (AT1) receptors and vascular angiotensin levels (Garcia, Shkolnik, Milhau, Falck, & Schwartzman, 2016; Wu, Gupta, Garcia, Ding, & Schwartzman, 2014). Likewise, Cyp4a12 transgenic and Cyp4a14 knockout mice have elevated 20-HETE levels that promote endothelial dysfunction and hypertension (Capdevila et al., 2007). The recent discovery of GPR75 as the 20-HETE receptor has further defined the contribution of vascular 20-HETE to hypertension (Garcia et al., 2017). 20-HETE dependent hypertension and endothelial dysfunction in Cyp4a12tg mice was attenuated by GPR75 knockdown (Garcia et al., 2017). Additional studies on GPR75 demonstrated that 20-HETE activation leads to increased vascular angiotensin converting enzyme which is consistent with findings in rats with CYP4A overexpression in endothelial cells (Garcia et al., 2017).

Pharmacological or genetic manipulation to increase vascular EETs or decrease vascular 20-HETE levels improves endothelial and vascular function to lower blood pressure in animal models of hypertension (Fan & Roman, 2017; Imig et al., 2020; Wu et al., 2013). Endothelial overexpression of CYP2J2 or CYP2C8 increased vascular EET levels, improved acetylcholine renal arteriolar dilation and opposed renal arteriolar endothelin constriction (Lee et al., 2010). Gene deletion of sEH also improved endothelial dependent renal arterioles in DOCA salt-sensitive hypertension (Manhiani et al., 2009). Likewise, EET analogs improved endothelial vasodilation and opposed angiotensin vasoconstriction in SHR and angiotensin hypertension (Hye Khan et al., 2014; Imig et al., 2010). Inhibition of 20-HETE lowers blood pressure in male and postmenopausal female SHR and angiotensin hypertension (Garcia et al., 2015; Yanes et al., 2011). Likewise, elevated blood pressure in Cyp4a12 transgenic and Cyp4a14 knockout mice is lowered by 20-HETE inhibition (Garcia et al., 2015; Wu et al., 2013). Taken together, these findings demonstrate that vascular EETs are antihypertensive and vascular 20-HETE is prohypertensive.

Diets rich in omega-3 EPA and DHA have actions to decrease vascular resistance (Colussi et al., 2017; Panda et al., 2022). These omega-3 fatty acids have antagonistic effects on AT1 receptors to attenuate hypertension (Farooq et al., 2020; Niazi et al., 2017). Increases in EPA COX and LO metabolites have vasodilator actions that oppose angiotensin vasoconstriction (Hui, Robillard, Grose, Lebel, & Falardeau, 1991; Niazi et al., 2017). Incorporation of EPA and DHA into membrane phospholipids increase arterial compliance to modulate vascular resistance (Cicero, Ertek, & Borghi, 2009; Sanders et al., 2011). EPA and DHA cause aortic dilation in SHR by enhancing endothelial nitric oxide production (van den Elsen et al., 2014). In addition, omega-3 fatty acids can decrease vascular TX and increase vascular PGI2 production (Bolton-Smith, Gibney, Vas Dias, & Hillier, 1984). Omega-3 epoxides have also been demonstrated to be antihypertensive (Schunck et al., 2018). Angiotensin hypertension is attenuated by omega-3 fatty acids and 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) vascular actions (Schunck et al., 2018; Ulu et al., 2014). 17,18-EEQ and 19,20-EDP can increase nitric oxide to cause vasodilation (Bercea, Cottrell, Tamagnini, & McNeish, 2021). Omega-3 fatty acid diets via acetylated COX-2 or CYP can also generate 18-hydroxyeicosapentaenoic acid (18-HEPE), the precursor of the E-series resolvins and17-hydroxydocosahexaenoic acid (17-HDHA), the precursor of the D-series resolvins (Serhan & Levy, 2018). Resolvins E1, D1, and D2 oppose TX constriction of rat aorta which could contribute to omega-3 fatty acid diet cardiovascular protective actions (Jannaway, Torrens, Warner, & Sampson, 2018). Interestingly, human studies have revealed that DHA but not EPA can have blood pressure lowering actions by improving endothelial function and reducing vasoconstriction in the forearm microcirculation (Zehr & Walker, 2018). These findings would suggest that DHA has a more potent vascular action to lower blood pressure in hypertension.

Other bioactive lipids that impact vascular resistance in hypertension include nitrated fatty acids, IsoLGs, and SCFAs. Nitro-oleic acid decreases angiotensin vascular reactivity by binding to the AT1 receptor to lower blood pressure in angiotensin hypertension (Zhang et al., 2010). Another vascular action for nitro-oleic acid is sEH inhibition which results in increased vascular EET levels (Charles et al., 2014). Nitro-oleic acid also preserves endothelial function via enhancing eNOS and heme-oxygenase-1 (HO-1) expression (Khoo et al., 2010). On the other hand, increases in IsoLG-protein adducts contribute to hypertension and have been found in the heart and aorta of mice with angiotensin hypertension (Dikalova et al., 2017; Prinsen et al., 2020). This accumulation of IsoLGs in cardiovascular cells contributes to the inflammatory mechanisms contributing to hypertension (Krishnan et al., 2022). In addition, SCFAs are key regulators of vascular resistance and blood pressure regulation in hypertension (Wu, Xu, Tu, & Gao, 2021; Wu et al., 2021; Xu et al., 2022). Acetate, propionate, and butyrate result in vasodilation (Wu, Xu, Tu, & Gao, 2021; Wu et al., 2021; Xu et al., 2022). SCFAs also enhance endothelial vasodilation in hypertension (Robles-Vera, Toral, & Duarte, 2020; Robles-Vera et al., 2020). These endothelial actions for SCFAs to lower blood pressure are in part mediated by GPR41 activation at the endothelial cell to increase nitric oxide levels (Li et al., 2021; Mishima & Abe, 2022). Collectively, these findings indicate that IsoLGs vascular actions are prohypertensive whereas nitro-fatty acids and SCFAs have antihypertensive vascular actions that are in part dependent on enhancing nitric oxide levels.

5. Kidney regulation by bioactive lipids in hypertension

The kidney is responsible for water and electrolyte homeostasis. Excessive water and electrolyte reabsorption by the kidney results in increased plasma volume which is counteracted by elevating blood pressure. This phenomenon is known as pressure natriuresis which when impaired leads to hypertension. Bioactive lipids regulate sodium and potassium epithelial transport along the segments of the nephron (Fig. 3) (Cheng & Harris, 2004; Fan & Roman, 2017; Imig, 2018). Experimental studies have found that COX and CYP metabolites regulate epithelial sodium and potassium channels to impact water and electrolyte balance and blood pressure (Cheng & Harris, 2004; Fan & Roman, 2017; Imig, 2018). These findings have led to development of potential antihypertensive drugs that target these arachidonic acid pathways.

Fig. 3.

Fig. 3

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Kidney juxtaglomerular apparatus and tubular actions of bioactive lipids: Pro-hypertensive COX-2 generation of PGE2 which acts on EP4 receptors results in activation of the pro-renin receptor (PRR) and increased renin. Anti-hypertensive PGE2 EP2 receptor, EETs, 20-HETE, and nitro-fatty acids act on epithelial transport to increase sodium excretion.

The actions of COX metabolites on sodium transport along the nephron make key contributions to blood pressure regulation (Cheng & Harris, 2004; Nasrallah, Hassouneh, & Hébert, 2016). In addition, COX metabolites are key regulators of renin at the juxtaglomerular cell (Cheng & Harris, 2004). COX-1 is expressed in mesangial cells, renal endothelial cells, epithelial cells including the cortical and medullary collecting ducts (Cheng & Harris, 2004). COX-2 is also expressed in the kidneys with predominant expression at the macula densa along with expression in the thick ascending limb of Henle and medullary interstitial cells (Cheng & Harris, 2004). The contribution of renal COX metabolites to blood pressure control became evident because long-term nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit COX have hypertensive effects (Grosser et al., 2017).

The predominant COX metabolite in the kidney is PGE2 (Nasrallah et al., 2016). PGE2 actions on renal hemodynamics and sodium transport importantly regulate blood pressure (Nasrallah et al., 2016). Under basal conditions, PGE2 acting via EP2 receptors has potent diuretic and natriuretic actions (Chen et al., 2008). EP2 receptor activation leads to increases in cyclic adenosine monophosphate (cAMP) levels in the kidney to lower blood pressure (Guan et al., 2007). PGE2 vasodilates renal arterioles and inhibits sodium absorption at the collecting duct resulting in natriuresis (Imig, Breyer, & Breyer, 2002). The experimental finding that EP2 receptor knockout mice develop salt-sensitive hypertension supports the important natriuretic contribution of PGE2 acting on EP2 receptors (Kennedy et al., 1999). Likewise, microsomal PGE2 synthase-1 (mPGES-1) genetic deletion in mice causes a greater elevation in blood pressure in DOCA-salt and angiotensin hypertension (Jia, Zhang, Zhang, Dong, & Yang, 2006). These findings support the notion that PGE2 actions on the EP2 receptor in the kidney are antihypertensive. On the other hand, interactions between COX-2 and PGE2 on renal medullary cells and renin release are hypertensive (Cheng & Harris, 2004). COX-2 expressed at the macula densa mediates renin release in response to a low salt diet (Yang et al., 2000). There is also mounting evidence that the (pro)renin receptor (PRR) and COX-2 stimulate the expression of each other in renal medullary cells and contribute to angiotensin hypertension (Wang, Sun, et al., 2020; Wang, Zhou, et al., 2020; Yang, 2015). Inhibition of COX-2 blocked angiotensin induced PRR and renin activity in cell culture (Wang, Sun, et al., 2020; Wang, Zhou, et al., 2020). Likewise, COX-2 inhibition eliminated upregulation of renal medullary PRR and lowered blood pressure in angiotensin hypertension (Wang, Sun, et al., 2020; Wang, Zhou, et al., 2020). PGE2 acting on the EP4 receptor appears to mediate the angiotensin induced PRR expression (Wang, Lu, et al., 2014; Wang, Zhang, et al., 2014). EP4 receptor antagonism attenuated angiotensin hypertension and decreased urinary renin levels (Wang, Lu, et al., 2014; Wang, Zhang, et al., 2014). Thus, EP2 receptor agonists and EP4 receptor antagonists have actions in the kidney that would be antihypertensive.

CYP metabolites of arachidonic acid have been extensively evaluated for biological actions in the kidney that impact renal hemodynamics, epithelial transport, sodium excretion and blood pressure regulation. The importance for 20-HETE and EETs to kidney function and blood pressure control has been demonstrated in animal models of hypertension and human hypertension (Fan & Roman, 2017; Imig, 2018). In particular, 20-HETE and EETs regulate sodium excretion and have been implicated in salt-sensitive regulation of blood pressure (Fan & Roman, 2017; Imig, 2018). Renal actions of EETs increase blood flow and enhance sodium excretion whereas 20-HETE acts on renal arterioles to decrease blood flow and acts on epithelial transport to increase sodium excretion (Fan & Roman, 2017; Imig, 2018). Therefore, the kidney biological actions of EETs are antihypertensive and those of 20-HETE on the renal arterioles are prohypertensive and 20-HETE actions on epithelial transport are antihypertensive.

Extensive experimental evidence has demonstrated in animal models of hypertension that a decrease in kidney EETs contributes to salt-sensitive hypertension (Imig et al., 2020). Epoxide levels in the kidney are dependent on rat CYP2C11 and CYP2C23 or mouse Cyp2c44 levels (Imig et al., 2020). Renal CYP epoxygenase activity is decreased in angiotensin hypertension, Lyon hypertensive rats, and transgenic hypertensive rats overexpressing both human renin and angiotensinogen genes (dTGR) (Kaergel et al., 2002; Messer-Letienne et al., 1999; Zhao, Pollock, Inscho, Zeldin, & Imig, 2003). Dahl salt-sensitive rats also demonstrate low EET biosynthetic activity and develop severe salt-sensitive hypertension (Liclican, McGiff, Falck, & Carroll, 2008). Elevations in kidney sEH protein levels resulting in decreased EET activity contribute to angiotensin hypertension (Zhao et al., 2004).

Under normal physiological conditions, CYP2C epoxygenases are increased in response to a high K+ or high Na+ diet (Capdevila et al., 2014; Wang, Lu, et al., 2014; Wang, Zhang, et al., 2014). This increase in CYP2C epoxygenases and production of EETs are essential for water and electrolyte homeostasis. Decreased EET levels in hypertension result in increased arteriolar resistance and enhanced sodium absorption (Liclican et al., 2008; Zhao et al., 2003). Cyp2c44 gene deficient mice develop salt-sensitive hypertension in response to a high K+ or high Na+ diet (Capdevila et al., 2014; Wang, Lu, et al., 2014; Wang, Zhang, et al., 2014). The lack of EETs in Cyp2c44 knockout mice results in hyperactive epithelial sodium channel (ENaC) and reduction in ERK1/2 and ENaC phosphorylation (Capdevila et al., 2014). EET actions on basolateral inwardly rectifying K+ channels result in cell membrane depolarization which reduces the driving force for sodium entry across the apical membrane (Capdevila et al., 2014; Wang, Lu, et al., 2014; Wang, Zhang, et al., 2014). This EET action on K+ channels would enhance sodium excretion and when EETs are decreased result in lower sodium excretion which could contribute to salt-sensitive hypertension (Capdevila et al., 2014; Wang, Lu, et al., 2014; Wang, Zhang, et al., 2014). 11,12-EET and 14,15-EET are the predominant EET regioisomers produced in rodent kidneys (Imig et al., 2020). 11,12-EET appears to be the EET responsible for inhibiting apical ENaC and basolateral K+ channels (Capdevila et al., 2014). Intriguingly, Cyp4a10 knockout mice have decreased renal Cyp2c44 epoxygenase levels and develop salt-sensitive hypertension (Nakagawa et al., 2006). The development of salt-sensitive hypertension when kidney EET levels are decreased is attenuated by inhibition of ENaC (Nakagawa et al., 2006). This finding suggests that EET actions on ENaC in the collecting duct are critical for salt regulation and blood pressure control. Taken together, conditions that decrease kidney EETs results in an inability for the kidney to respond to a high K+ or high Na+ diet resulting in enhanced ENaC and K+ channel activity and salt-sensitive hypertension.

Although 20-HETE actions on the renal and systemic arterioles is prohypertensive, 20-HETE acts on epithelial transport to enhance sodium excretion and lower blood pressure (Fan & Roman, 2017). 20-HETE inhibits the Na+/K+ ATPase in the proximal tubule and thick ascending loop of Henle to increase sodium excretion (Kirchheimer, Mendez, Acquier, & Nowicki, 2007; Nowiki et al., 1997). 20-HETE increases PKC levels which phosphorylate Na+/K+ ATPase to inhibit activity (Nowiki et al., 1997). Renal 20-HETE also acts to internalize Na+/H+ exchanger 3 (NHE3) in the proximal tubule to promote pressure natriuresis (Dos Santos, Dahly-Vernon, Hoagland, & Roman, 2004; Zhou et al., 2006). Decreased renal tubular CYP4A protein and 20-HETE production contributes to salt-sensitive hypertension in Dahl rats (Ito & Roman, 1999; Roman et al., 2006). These findings along with those on EETs demonstrate that Dahl salt-sensitive hypertension results from decreased EET and 20-HETE levels (Fan & Roman, 2017; Imig et al., 2020). Induction of kidney 20-HETE and EETs by fibrates or transfer of wild-type CYP4A alleles to increase 20-HETE in the Dahl salt-sensitive rats improves sodium excretion and lowers blood pressure (Alonso-Galicia, Frohlich, & Roman, 1998; Roman, Ma, Frohlich, & Markham, 1993; Williams et al., 2008). These findings are in agreement with findings in humans that mutations inactivating CYP4A11 and CYP4F2 or lowering 20-HETE levels are associated with salt-sensitive hypertension (Gainer et al., 2005; Geng et al., 2019; Williams et al., 2011).

There is limited evidence for renal actions of LO, omega-3 fatty acids, SCFAs, nitro-fatty acids, and Iso-LGs to regulate water and electrolyte homeostasis and blood pressure. LO metabolites can influence tubular transport at various sites along the nephron (Dobrian et al., 2011). 12S-HETE enhances PKC phosphorylation of the Na+/K+ ATPase to inhibit activity (Friedlander, Le Grimellec, Sraer, & Amiel, 1990). Metabolites of 5-LO regulate isovolumetric water transport at the proximal tubule (Landgraf et al., 2014). LTD4 actions at the kidney result in increased urine and sodium excretion (Han, Park, Lee, Lee, & Park, 1999; Hebert et al., 1987). Nevertheless, the consequences of LO metabolite actions on renal tubular function to blood pressure regulation and hypertension remain unknown. Omega-3 fatty acids and EPA and DHA metabolite actions at the kidney have not been evaluated. Because EPA and DHA metabolites can act on vascular sodium channels, they could potentially act on tubule transport and alter urinary electrolyte excretion (Ander et al., 2007; Mayol et al., 1999). Although nitro-fatty acids have not been demonstrated to directly act to alter epithelial sodium transport, nitro-fatty acids inhibit sEH activity (Charles et al., 2014). This inhibition of sEH activity could lead to increased EET levels in the kidney resulting in enhanced sodium excretion and lowering of blood pressure. Like nitro-fatty acids, IsoLGs actions on renal epithelial transport have not been investigated. Interestingly, elevated sodium is a potent stimulus for IsoLGs protein adduct formation in mice dendritic cells (Elijovich et al., 2021; Ertuglu & Kirabo, 2022). This increase in dendritic cell IsoLGs is via an amiloride sensitive sodium transporter (Ertuglu & Kirabo, 2022). Collectively, there is limited investigation into LO, omega-3 fatty acids, SCFAs, nitro-fatty acids, and Iso-LGs on epithelial transport to regulate blood pressure in hypertension.

6. Inflammation and bioactive lipids in hypertension

Inflammation is recognized as a key contributor to vascular and kidney function as well as blood pressure regulation. The contribution of inflammation to hypertension, kidney, and cardiovascular diseases is well established (Harrison, Coffman, & Wilcox, 2021; Van Beusecum, Moreno, & Harrison, 2022). Human studies established a correlation between inflammation and cardiovascular diseases (Harrison et al., 2021). Experimental studies in animal models of hypertension have clearly demonstrated that an increase in inflammatory cytokines and infiltration of immune cells into the vasculature and kidney contribute to hypertension (Harrison et al., 2021; Van Beusecum et al., 2022). In addition, bioactive lipids have been recognized for at least six decades as important regulators of inflammation (Capra et al., 2013; Khanapure, Garvey, Janero, & Letts, 2007; Yamaguchi, Botta, & Holinstat, 2022). COX metabolites were the first bioactive lipids recognized for inflammatory actions (Grosser et al., 2017). Aspirin and COX inhibitors act as NSAIDs to combat fever and inflammatory pain (Grosser et al., 2017). It is now recognized that COX, LO, CYP, omega-3 fatty acids, SCFAs, nitro-fatty acids, and Iso-LGs can have pro-inflammatory and anti-inflammatory actions (Fig. 4). Manipulation of bioactive lipids to regulate inflammation has become therapeutic option for hypertension and cardiovascular diseases (Imig, 2018; Van Beusecum et al., 2022).

Fig. 4.

Fig. 4

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Bioactive lipids have pro-inflammatory and anti-inflammatory actions: Pro-inflammatory bioactive lipids increase inflammation that generates reactive oxygen species (ROS), causes vasoconstriction and endothelial function, and sodium retention which contribute to hypertension. Several anti-inflammatory bioactive lipids act to decrease inflammation to combat hypertension.

Contrary to the idea that inflammation contributes to hypertension anti-inflammatory NSAIDs that inhibit COX have hypertensive actions Grosser et al., 2017). On the other hand, DOCA-salt hypertension is attenuated in mice lacking PGES1 (Jia et al., 2006). This lowering of blood pressure in DOCA-salt hypertension is likely due to pro-hypertensive kidney actions of PGE2 rather than effects on inflammation (Jia et al., 2006). Unlike PGE2 generation by mPGES1, EP2 receptor genetic deficiency in mice demonstrates an anti-hypertensive action for PGE2 activation of EP2 receptors (Kennedy et al., 1999). A link to inflammation and the PGE2 EP2 receptor axis could be the regulation of NADPH oxidase and reactive oxygen species (Jia et al., 2008). PGE2 inhibits reactive oxygen species production in angiotensin hypertension (Jia et al., 2008). Another COX metabolite, TX acting on TP receptors is pro-hypertensive and increases oxidative stress (Matsumoto et al., 2015; Wilcox, 2002). A link between TX and inducible nitric oxide synthase which induces cytokines has been established in sepsis (Virdis et al., 2005). Lastly, PGI2 vascular anti-inflammatory could be a key reason that COX-2 inhibitors increase blood pressure and cardiovascular events (Mitchell & Kirkby, 2019; Matsumoto et al., 2015). Mice with either endothelial or vascular smooth muscle cell specific deletion of COX-1 had decreased PGI2 generation which accelerated thrombosis and elevated blood pressure (Mitchell et al., 2019; Mitchell et al., 2021). Taken together, the findings in animals and humans demonstrate a complex action of COX metabolites and receptors on inflammation and blood pressure control.

The contribution of LO metabolites to inflammation and blood pressure control in hypertension has been clearly established (Singh & Rao, 2019). 12-LO and 15-LO are elevated in humans with essential hypertension and several animal models of hypertension (Kim et al., 2013; Quintana et al., 2006; Singh & Rao, 2019). It is also well known that macrophages generate LO metabolites in experimental hypertension (Singh & Rao, 2019). Alox15−/− mice demonstrate decreased blood pressure in L-NAME and DOCA-salt hypertension (Kriska et al., 2012). The lowering of blood pressure was due to macrophage generated 12-HETE and 15-HETE since injection of wild-type macrophages into 15-LO (Alox15)−/− mice with L-NAME hypertension lacked a decrease in blood pressure (Kriska et al., 2012). Inflammatory cytokines that are decreased in Alox15−/− mice include interleukin (IL) IL-12 and interferon-γ (IFN-γ) (Martínez-Clemente et al., 2010; Zhao et al., 2002). Alox15 generated 12-HETE and 12-HPETE increase the expression of pro-inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), IL-12, and IL-6 (Kriska et al., 2012; Martínez-Clemente et al., 2010). Interestingly, gene deficiency or blockade of these cytokines has been demonstrated to decrease blood pressure in rodent hypertensive models (Elmarakby et al., 2007; Elmarakby, Quigley, Imig, Pollock, & Pollock, 2008; Kriska et al., 2012).

The polarization of macrophages could also play a key role in regulation of LO metabolites in hypertension. M1 macrophage generation of 12S-HETE can enhance angiotensin vasoconstriction whereas M2 converted 12S-HETE into products that failed to enhance angiotensin vascular reactivity (Kriska et al., 2022). The M1 macrophage generated 12S-HETE enhances angiotensin II vascular reactivity through activation of the LTB4 type 2 receptor (BLT2) and TP receptor (Kriska et al., 2022). Likewise, a BLT2 receptor antagonist prevented angiotensin hypertension (Kriska et al., 2022). These findings point to the pro-hypertensive actions of M1 generated 12S-HETE acting on vascular BLT2 and TP receptors.

CYP EET metabolites have been demonstrated to be anti-inflammatory whereas CYP 20-HETE generation is pro-inflammatory (Fan & Roman, 2017; Imig, 2018). These CYP metabolite actions have been demonstrated to contribute to blood pressure control in hypertension (Fan & Roman, 2017; Imig, 2018). EETs decrease vascular inflammation through inhibition of NF-κB (Dong et al., 2017; Node et al., 1999). In the other direction, decreased EET levels or increased sEH activity contributes to kidney and vascular inflammation in rodent DOCA-salt and angiotensin hypertension (Manhiani et al., 2009; Zhao et al., 2004). Increasing EET levels decreases kidney macrophage infiltration in hypertension and lowers blood pressure (Manhiani et al., 2009; Zhao et al., 2004). Kidney cytokine IL-6, TNF-α, and MCP-1 levels are decreased by EETs in animal models of hypertension (Manhiani et al., 2009; Zhao et al., 2004). Thus, increasing EET levels in hypertension results in decreased vascular and kidney inflammation which contributes to the EET anti-hypertensive actions. On the contrary is the vascular pro-inflammatory actions of 20-HETE. 20-HETE increases vascular inflammation at the endothelial cell which increases cytokines and adhesion molecules (Fan et al., 2016; Froogh, Garcia, & Laniado Schwartzman, 2022). This action of 20-HETE is through the 20-HETE receptor GPR75 (Froogh et al., 2022); however, the contribution of 20-HETE action on vascular inflammation to hypertension remains to be explored.

Omega-3 fatty acids, SCFAs, nitro-fatty acids, and Iso-LGs have inflammatory actions which could contribute to hypertension. The anti-inflammatory actions of omega-3 fatty acids and EPA and DHA metabolites has been well established (Colussi et al., 2017; Panda et al., 2022). Fish oil supplements, EPA, and DHA reduce IL-6, IL-1β, C-reactive protein, MCP-1, and TNF-α (Colussi et al., 2017; Panda et al., 2022). These anti-inflammatory actions could be due to increased levels of 18-HEPE, 17-HDHA, and resolvins (Serhan & Levy, 2018). Human studies have demonstrated that omega-3 fatty acid diets increase these EPA and DHA metabolites and these metabolites associate with decreased inflammation in major depressive disorder, arthritis, and chronic kidney disease (Barden et al., 2016; Lamon-Fava et al., 2021; Mas et al., 2016). Indeed, resolvin-D1 attenuates inflammation and lowers blood pressure in angiotensin hypertension (Olivares-Silva et al., 2021). SCFAs can act at GPR43 to effect immune cells and GPR43 is differentially expressed in human essential hypertension (Xu et al., 2022). Interestingly, propionate attenuates the response to T cells in angiotensin hypertension and lowers blood pressure (Bartolomaeus et al., 2019). Butyrate can also decrease IL-6 and TNF-α levels resulting in decreased blood pressure in hypertension (Wu, Xu, Tu, & Gao, 2021; Wu et al., 2021; Zhang et al., 2019). SCFAs can also decrease T helper 17 (Th17) and IL-17 levels in humans with hypertension (Robles-Vera, Toral, & Duarte, 2020; Robles-Vera et al., 2020); however, the effect on blood pressure was not determined. Nitro-fatty acids have anti-inflammatory actions that could lower blood pressure in hypertension (Mollenhauer et al., 2018). Intriguingly, these anti-inflammatory actions for nitro-fatty acids are via inhibition of sEH activity and increasing EET levels (Charles et al., 2014). Lastly, IsoLGs accumulate in dendritic cells and are activated to produce pro-inflammatory cytokines IL-1β, IL-6, and IL-23 which contribute to human salt-sensitive hypertension (Elijovich et al., 2021; Ertuglu & Kirabo, 2022). Scavenging of IsoLGs can prevent kidney T cell infiltration and lower blood pressure in hypertensive mice (Pitzer et al., 2022). Taken together, these findings demonstrate that bioactive lipid pro-inflammatory or anti-inflammatory actions can contribute to blood pressure regulation and hypertension.

7. Conclusion

The vascular, kidney, and inflammatory actions of bioactive lipids can impact blood pressure regulation in hypertension. These actions can be pro-hypertensive or anti-hypertensive depending on the fatty acid, enzymatic pathway, metabolites generated, and receptors activated. Arachidonic acid metabolites of the COX, LO, and CYP have been extensively evaluated for biological actions that impact blood pressure regulation.

Intriguingly, metabolites and receptors from the COX, LO, or CYP pathway can have pro-hypertensive or anti-hypertensive actions depending on the tissue that they act upon. These findings have identified approaches for the management and treatment of hypertension. Although NSAIDs and COX inhibitors negatively impact treatment of hypertension, there are COX metabolites and their receptors that demonstrate potential for hypertension treatment (Grosser et al., 2017; Nasrallah et al., 2016; Wang, Lu, et al., 2014; Wang, Zhang, et al., 2014). Inhibition of vascular TX and PGE2 EP1 receptor are anti-hypertensive and decrease cardiovascular events (Francois et al., 2004; Guan et al., 2007). The kidney epithelial sodium transport and PRR actions of PGE2 on EP2 and EP4 receptors impact blood pressure regulation (Kennedy et al., 1999; Wang, Lu, et al., 2014; Wang, Zhang, et al., 2014). EP2 receptor agonists act to increase sodium excretion and lower blood pressure which could be beneficial for salt-sensitive hypertension (Kennedy et al., 1999). On the other hand, EP4 receptor antagonists act to decrease renin levels which could combat angiotensin dependent hypertension (Wang, Lu, et al., 2014; Wang, Zhang, et al., 2014). COX metabolite actions on inflammation are complex and have failed to provide an approach for hypertension treatment. LO metabolites and receptors have inflammatory actions that impact vascular reactivity could be exploited for the management and treatment of hypertension (Kriska et al., 2022; Singh & Rao, 2019). Inhibitors for 15-LO, 12S-HETE, or BLT2 receptor are potential treatment approaches that would decrease inflammation, improve vascular function, and lower blood pressure in hypertension. CYP vascular, kidney, and inflammatory actions also provide potential treatments for hypertension (Imig, 2018). EET agonists and sEH inhibitors decrease vascular resistance, increase sodium excretion, and decrease inflammation in hypertension (Imig, 2018). Positive vascular and inflammatory actions for manipulating EETs with sEH inhibition has clearly been demonstrated in humans with chronic obstructive pulmonary disease (Yang et al., 2017). Inhibition of 20-HETE or GPR75 vascular and inflammatory actions have anti-hypertensive actions; however, 20-HETE agonists acting on renal epithelial cells could be beneficial in salt-sensitive hypertension (Fan & Roman, 2017; Froogh et al., 2022). The prevailing evidence would suggest that inhibiting 20-HETE vascular and inflammatory actions provides a better therapeutic approach for the management and treatment of hypertension (Froogh et al., 2022; Imig, 2020).

Other bioactive lipids include omega-3 fatty acids, IsoLGs, nitrated fatty acids, and SCFAs that can also impact vascular, kidney, or inflammatory function to impact blood pressure regulation. The vascular and inflammatory actions for omega-3 fatty acids EPA and DHA can be beneficial for the management and treatment of hypertension (Colussi et al., 2017; Schunck et al., 2018). This can be achieved through dietary changes or taking fish oil supplements (Colussi et al., 2017; Panda et al., 2022). In addition, the actions of specific EPA and DHA metabolites and synthetic agonists are being investigated for anti-hypertensive and cardiovascular protective actions (Schunck et al., 2018). Resolvins generated from 18-HEPE and 17-HDHA also have anti-hypertensive actions in pulmonary arterial hypertension and angiotensin hypertension (Diaz del Campo et al., 2023; Liu et al., 2021; Olivares-Silva et al., 2021). Scavenging IsoLGs to prevent kidney T cell infiltration is a potential therapeutic approach to treat salt-sensitive hypertension (Elijovich et al., 2021). Vascular and inflammatory actions for nitrated fatty acids lower blood pressure in animal models of hypertension (Mollenhauer et al., 2018). Drug candidates for nitrated fatty acids have been developed. Interestingly, 10-NO2-OA (CXA-10) has advanced to clinical trials for the treatment of pulmonary arterial hypertension (Garner, Mould, Chieffo, & Jorkasky, 2019; Schopfer, Vitturi, Jorkasky, & Freeman, 2018). SCFAs vascular actions to lower blood pressure have identified GPR41 as a potential target for the management and treatment of hypertension (Li et al., 2021; Mishima & Abe, 2022). Anti-inflammatory actions described for SCFAs could also be beneficial for hypertension (Bartolomaeus et al., 2019; Xu et al., 2022).

Experimental studies continue to determine the impact of bioactive lipids on blood pressure regulation. Manipulating enzymes, metabolites, and receptors of bioactive lipids has demonstrated promise to manage and treat hypertension and associated metabolic, renal and cardiovascular diseases. In summary, bioactive lipids and their manipulation represent an expanding area of research that has potential to be beneficial to the management and treatment of hypertension and other cardiovascular diseases.

Acknowledgments

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases DK126452 and Arkansas Research Alliance. Servier Medical Art was used to generate Figs. 2, 3, and 4 and is licensed by Servier under a Creative Commons Attribution 3.0 Unported License.

Abbreviations

(PTGS2)

COX-2

17,18-EEQ

17,18-epoxyeicosatetraenoic acid

17-HDHA

17-hydroxydocosahexaenoic acid

18-HEPE

18-hydroxyeicosapentaenoic acid

19,20-EDP

19,20-epoxydocosapentaenoic acid

DHETs

dihydroxyeicosatrienoic acids

dTGR

transgenic hypertensive rats overexpressing human renin and angiotensinogen genes

EETs

epoxyeicosatrienoic acids

FADS

fatty acid desaturase

HETEs

hydroxyeicosatetraenoic acids

IsoLGs

isolevuglandins

PRR

(pro)renin receptor

PTGER2

prostaglandin E2 receptor EP2

SCFAs

short chain fatty acids

sEH

soluble epoxide hydrolase

Footnotes

Conflict of interest statement

Dr. Imig has patents that cover the composition of matter for EET analogs. There are no other conflicts of interest, financial or otherwise, are declared by the author.

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