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

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