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Anti-Inflammatory Effects of V-3 Polyunsaturated Fatty Acids And

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Anti-Inflammatory Effects of V-3 Polyunsaturated Fatty Acids And ORIGINAL ARTICLE Anti-inflammatory Effects of v-3 Polyunsaturated Fatty Acids and Soluble Epoxide Hydrolase Inhibitors in Angiotensin-II–Dependent Hypertension Arzu Ulu, MSc,* Todd R. Harris, PhD,* Christophe Morisseau, PhD,* Christina Miyabe, BS,* Hiromi Inoue, DVM,† Gertrud Schuster, PhD,‡ Hua Dong, PhD,* Ana-Maria Iosif, PhD,§ Jun-Yan Liu, PhD,* Robert H. Weiss, MD,†¶ Nipavan Chiamvimonvat, MD,k¶ John D. Imig, PhD,** and Bruce D. Hammock, PhD* renal markers of inflammation (ie, prostaglandins and MCP-1), Abstract: The mechanisms underlying the anti-inflammatory and downregulated an epithelial sodium channel, and upregulated angioten- antihypertensive effects of long-chain v-3 polyunsaturated fatty acids sin-converting enzyme-2 message and significantly modulated cyclo- (v-3 PUFAs) are still unclear. The epoxides of an v-6 fatty acid, oxygenase and lipoxygenase metabolic pathways. Overall, our findings arachidonic acid epoxyeicosatrienoic acids also exhibit antihyperten- suggest that epoxides of the v-3 PUFAs contribute to lowering systolic sive and anti-inflammatory effects. Thus, we hypothesized that the blood pressure and attenuating inflammation in part by reduced pros- major v-3 PUFAs, including eicosapentaenoic acid (EPA) and doco- taglandinsandMCP-1andbyupregulation of angiotensin-converting sahexaenoic acid (DHA), may lower the blood pressure and attenuate enzyme-2 in angiotensin-II–dependent hypertension. renal markers of inflammation through their epoxide metabolites. v Here, we supplemented mice with an v-3 rich diet for 3 weeks in Key Words: -3 polyunsaturated fatty acids, EPA, DHA, soluble – a murine model of angiotensin-II–dependent hypertension. Also, epoxide hydrolase inhibitors, angiotensin-II dependent hypertension because EPA and DHA epoxides are metabolized by soluble epoxide (J Cardiovasc PharmacolÔ 2013;62:285–297) hydrolase (sEH), we tested the combination of an sEH inhibitor and the v-3 rich diet. Our results show that v-3 rich diet in combination with the sEH inhibitor lowered Ang-II, increased the blood pressure, INTRODUCTION further increased the renal levels of EPA and DHA epoxides, reduced Cardiovascular disease (CVD) is one of the main causes of death worldwide, and thus is the subject of numerous studies to explore potential new treatment strategies. Cardiovascular risk of Received for publication August 13, 2012; accepted April 24, 2013. From the *Department of Entomology and UC Davis Comprehensive Cancer stroke, coronary artery disease, and hypertensive end-organ 1 Center, University of California, Davis, CA; †Division of Nephrology; damage is increased by hypertension. High blood pressure (BP) ‡Department of Nutrition; kDivision of Cardiovascular Medicine, Depart- can be reduced by certain dietary modifications, such as an ment of Internal Medicine; §Division of Biostatistics, Department of Public increased consumption of long-chain v-3 polyunsaturated fatty Health Sciences, School of Medicine, University of California, Davis, v fi fi 2 USA; ¶US Department of Veterans’ Affairs Medical Center, Sacramento, acids ( -3 PUFAs) found in fatty sh or sh oil. The American CA; and **Department of Pharmacology and Toxicology, Medical College Heart Association recommends that healthy adults consume of Wisconsin, Milwaukee, WI. a serving of fish at least 2 times a week and patients with Supported by NIEHS grant R01 ES002710 and NIEHS Superfund Research coronary heart disease take a supplement of 1 g of eicosapentae- Program grant P42 ES004699; NIH grants 5UO1CA86402 (Early Detection noic acid (EPA) (20:5) and docosahexaenoic acid (DHA), 22:6 Research Network), 1R01CA135401-01A1, and 1R01DK082690-01A1; and 3 v the Medical Service of the US Department of Veterans’ Affairs (all to R.H. every day. In addition to hypertension, the long-chain -3 PU- 4,5 W.). Analytical work was partially supported by the NIH and NIDDK grant FAs have the potential to protect against many CVDs, espe- U24 DK097154. Studies and analyses performed by J. D. Imig were sup- cially coronary heart disease and atrial fibrillation. These fatty ported by NIH grants HL59699 and DK38226. Analyses performed by A.-M. acids have been shown to exert anti-inflammatory,6–8 antiathero- Iosif were supported by the National Center for Advancing Translational 9 2,10–12 Sciences, NIH, through grant UL1 TR000002. T. R. Harris is supported by sclerotic, and antiarrhythmic effects. There is a general NIH T32 training grant in basic and translational cardiovascular science (T32 feeling that consumption of v-3 lipids reduces cardiovascular HL86350). B. D. Hammock is a George and Judy Marcus senior fellow of the risk; however, some of the individual studies lack power to draw American Asthma Foundation, and was supported by NIEHS grant R01 solid conclusions, whereas some others have failed to show ES002710 and NIEHS Superfund Research Program grant P42 ES004699. efficacy.13–17 The mechanisms of action of v-PUFAs are not The University of California, Davis, has filed patents in the area of soluble epoxide hydrolase inhibitors for the treatment of diseases. well understood. Supplemental digital content is available for this article. Direct URL citations In the v-6 fatty acid series, metabolites of arachidonic appear in the printed text and are provided in the HTML and PDF acid (ARA) are well known to influence inflammation and versions of this article on the journal’s Web site (www.jcvp.org). CVD.18–20 Of particular interest, the epoxides of ARA [epox- Reprints: Bruce D. Hammock, PhD, One Shields Avenue, Department of fl Entomology, University of California, Davis CA 95616 (e-mail: yeicosatrienoic acids (EETs)] have anti-in ammatory and anti- [email protected]) hypertensive properties similar to the ones observed with the – Copyright © 2013 by Lippincott Williams & Wilkins long-chain v-3 PUFAs.21 23 Moreover, in vitro DHA epoxides J Cardiovasc Pharmacolä Volume 62, Number 3, September 2013 www.jcvp.org | 285 Ulu et al J Cardiovasc Pharmacolä Volume 62, Number 3, September 2013 [epoxydocosapentaenoic acids (EpDPEs)], similar to EETs, using the C57/BL6 strain, which is poorly responsive to Ang-II activate a large-conductance Ca2+-activated K+ channel24,25 compared to some other strains of mice.32 Instead, we used that lead to vasodilatation ex vivo.26 Recently, regioisomeric Swiss Webster mice, in which the oxylipin profiles and the mixtures of EPA epoxides [epoxyeicosatetraenoic acids pharmacokinetics of the sEHIs have been well characterized,33,34 (EpETEs)] and EpDPEs were shown to reduce inflammatory and who do not develop renal damage induced by angiotensin-II. pain, in which EpDPEs were demonstrated to be more effective This allowed examining the effects of the v-3 PUFAs solely on in reducing the nociceptive pain than the EpETEs and EETs.27 changes in the BP and in renal eicosanoids. Eight week old male Interestingly, the regioisomers of DHA epoxides show unequal Swiss Webster mice (Charles River Laboratories, Wilmington, effects on inflammatory pain. The bioactive v-3 PUFAs com- MA) were acclimated to new housing conditions for 1 week and pete with ARA for metabolism by cytochrome P450 enzymes were kept under a 12 hour light–dark cycle with free access to (CYP), specifically CYP2C and 2J, which largely generate the water and food for the duration of the experiment. Baseline BPs EETs.28,29 Based on these observations, we hypothesized that were established for each group of mice based on the average BP EPA and DHA lower arterial BP and attenuate renal markers of taken for 3 days before treatment. Hypertension was induced inflammation in vivo at least in part through their epoxide by infusion of Ang-II at a constant rate (20 ng/min or metabolites in angiotensin-II–dependent hypertension. To 1mg21$kg21$d21) for 14 days using subcutaneously implanted address this hypothesis, we conducted an experiment that osmotic minipumps (Model 1002-Alzet, Cupertino, CA). included controls and Ang-II–infused animals with and without Mice were fed either a purified control diet (5% corn an v-3 rich diet. We predicted that hypertensive animals trea- oil) or an v-3 rich diet consisting of the 2 major long-chain ted with an v-3 rich diet will have lower BP as compared to v-3 fatty acids, EPA (0.75%) and DHA (0.75%) at 90% their Ang-II–infused counterparts. Like the EETs, the EPA and purity (Larodan Fine Chemicals, Sweden). In the control diet, DHA epoxides are very good substrates for the soluble epoxide v-3 fatty acids replaced corn oil to retain constant dietary fat. hydrolase (sEH).27 Such hydrolytic metabolism has been The detailed composition and preparation of the diets are shown to reduce the bioactivity of EETs,30,31 and it should also given in Supplemental Digital Content 1 (see Table S1A, reduce the bioactivity of these CYP-generated epoxy fatty http://links.lww.com/JCVP/A121). Based on the fatty acid acids (EpFAs) that are derived from EPA and DHA. Conse- analysis of each diet (see Section A, Supplemental Digital quently, we tested the additional hypothesis that the presence Content 1, http://links.lww.com/JCVP/A121, which de- of an sEH inhibitor (sEHI) will further increase the effective- scribes the method for fatty acid analysis), the total percent- ness of the parent compounds by increasing the tissue levels of age of the v-3 PUFAs was 0.6% and 23% for corn oil and the epoxide metabolites, EpDPEs and EpETEs. To address v-3 rich diet, respectively (Table S1B, which presents the these additional hypotheses, we also included Ang-II–infused fatty acid composition of the v-3 rich diet). Animals were animals treated with the combination of v-3 rich diet and sEHI randomly divided into 6 experimental groups: Animals in the (at low and high doses) and those treated only with the sEHI to control group underwent sham surgery and the vehicle treat- control for the potential antihypertensive effect of the sEHI. ment, drinking water with 1% PEG400.
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