Anti-inflammatory Effects of ω-3 Polyunsaturated Fatty Acids and Soluble Epoxide Hydrolase Inhibitors in Angiotensin-II–Dependent Hypertension

Abstract

The mechanisms underlying the anti-inflammatory and anti-hypertensive effects of long chain ω-3 polyunsaturated fatty acids (PUFAs) are still unclear. The epoxides of an ω-6 fatty acid, arachidonic acid (epoxyeicosatrienoic acids; EETs) also exhibit anti-hypertensive and anti-inflammatory effects. Thus, we hypothesized that the major ω-3 PUFAs including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may lower blood pressure and attenuate renal markers of inflammation through their epoxide metabolites. Here, we supplemented mice with an ω-3 rich diet for three weeks in a murine model of angiotensin-II dependent hypertension. Also, since EPA and DHA epoxides are metabolized by soluble epoxide hydrolase (sEH), we tested the combination of a sEH inhibitor and the ω-3 rich diet. Our results show that ω-3 rich diet in combination with the sEH inhibitor lowered Ang-II increased blood pressure, further increased renal levels of EPA and DHA epoxides, reduced renal markers of inflammation (i.e. prostaglandins and MCP-1), down-regulated an epithelial sodium channel and up-regulated Angiotensin converting enzyme-2 message (ACE-2) and significantly modulated cyclooxygenase and lipoxygenase metabolic pathways. Overall, our findings suggest that epoxides of the ω-3 PUFAs contribute to lowering SBP and attenuating inflammation in part by reduced prostaglandins and MCP-1 and by up-regulation of ACE-2 in angiotensin-II dependent hypertension.

Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway

“…BK channels are also the main effector of the vasodilatory action of CYP-epoxygenase metabolites ( 18,25,(70)(71)(72), suggesting that the effects attributed to n-3 PUFAs might actually be mediated by the increased formation of EEQs and EDPs. In line with this hypothesis, pharmacological sEH inhibition increased the endogenous levels of EEQs and EDPs and enhanced the antihypertensive effect of EPA/DHA supplementation in angiotensin II-hypertensive mice ( 73 ). Moreover, Cyp1a1 knockout mice showed elevated blood pressure and reduced vasodilation to n-3 PUFAs, presumably due to reduced production of 17,18-EEQ and 19,20-EDP ( 74 ).…”

Effect of soluble epoxide hydrolase polymorphism on substrate and inhibitor selectivity and dimer formation

“…Interestingly, the concentrations of EpFAs in tissues are usually in the low nanomolar range ( 1,18,19 ), suggesting that in tissues the amount of sEH activity is not the limiting factor for the conversion of EpFAs, but likely the accessibility to these substrates, like for most hydrolases. Thus, SNPs that slightly (<3-fold) increase (K55R and C154Y) or decrease (R103C) the sEH activity probably do not effectively change the apparent metabolism of EpFAs in tissues.…”

“…There is no indication in the literature that the pathologies associated with the other SNPs resulted from altered EpFA metabolism (11)(12)(13)(14). Separately, the observation that in some tissues the concentration of sEH ( Table 3 ) is higher than its natural substrates ( 1,18,19 ) suggests that >90% inhibition of the enzyme is needed to signifi cantly alter EpFA metabolism is some tissues, such as the liver and kidneys.…”

“…Like the EETs, the n-3 EpFAs are biologically active ( 1 ). Interestingly, while for infl ammation and pain the EETs and n-3 EpFAs have similar effects ( 18,19 ), EETs and EpDPEs have opposite effects on angiogenesis, with the former promoting it and the latter reducing it ( 20 ). Although the sEH SNPs were shown to change the enzyme specifi c activity ( 10 ), their effects on substrate selectivity, which can alter the biological role of sEH, have not been tested.…”

Soluble Epoxide Hydrolase as an Anti-inflammatory Target of the Thrombolytic Stroke Drug SMTP-7

“…EETs are signaling molecules implicated in anti-inflammation (57,58). SMTP-7 and its congeners inhibited the hydrolysis of 14,15-EET to the inactive 14,15-DHET in HepG2 cells (Fig.…”