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      Aberrant Soluble Epoxide Hydrolase and Oxylipin Levels in a Porcine Arteriovenous Graft Stenosis Model

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          Synthetic arteriovenous grafts (AVGs) used for hemodialysis frequently fail due to the development of neointimal hyperplasia (NH) at the vein-graft anastomosis. Inflammation and smooth-muscle cell (SMC) and myofibroblast proliferation and migration likely play an important role in the pathogenesis of NH. Epoxyeicosatrienoic acids (EETs), the products of the catabolism of arachidonic acid by cytochrome P450 enzymes, possess anti-inflammatory, antiproliferative, antimigratory and vasodilatory properties that should reduce NH. The degradation of vasculoprotective EETs is catalyzed by the enzyme, soluble epoxide hydrolase (sEH). sEH upregulation may thus contribute to NH development by the enhanced removal of vasculoprotective EETs. In this study, sEH, cytochrome P450 and EETs were examined after AVG placement in a porcine model to explore their potential roles in AVG stenosis. Increased sEH protein expression, decreased P450 epoxygenase activity and dysregulation of 5 oxylipin mediators were observed in the graft-venous anastomotic tissues when compared to control veins. Pharmacological inhibitors of sEH decreased the growth factor-induced migration of SMCs and fibroblasts, although they had no significant effect on the proliferation of these cells. These results provide insights on epoxide biology in vascular disorders and a rationale for the development of novel pharmacotherapeutic strategies to prevent AVG failure due to NH and stenosis.

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          Most cited references 62

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          Epoxygenase pathways of arachidonic acid metabolism.

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            Hemodialysis vascular access dysfunction: a cellular and molecular viewpoint.

            Hemodialysis vascular access dysfunction is a major cause of morbidity and hospitalization in the hemodialysis population. The major cause of hemodialysis vascular access dysfunction is venous stenosis as a result of neointimal hyperplasia. Despite the magnitude of the clinical problem, however, there has been a paucity of novel therapeutic interventions in this field. This is in marked contrast to a recent plethora of targeted interventions for the treatment of arterial neointimal hyperplasia after coronary angioplasty. The reasons for this are two-fold. First there has been a relative lack of cellular and molecular research that focuses on venous neointimal hyperplasia in the specific setting of hemodialysis vascular access. Second, there have been inadequate efforts by the nephrology community to translate the recent advances in molecular and interventional cardiology into therapies for hemodialysis vascular access. This review therefore (1) briefly examines the different forms of hemodialysis vascular access that are available, (2) describes the pathology and pathogenesis of hemodialysis vascular access dysfunction in both polytetrafluoroethylene grafts and native arteriovenous fistulae, (3) reviews recent concepts about the pathogenesis of vascular stenosis that could potentially be applied in the setting of hemodialysis vascular access dysfunction, (4) summarizes novel experimental and clinical therapies that could potentially be used in the setting of hemodialysis vascular access dysfunction, and, finally, (5) offers some broad guidelines for future innovative translational and clinical research in this area that hopefully will reduce the huge clinical morbidity and economic costs that are associated with this condition.
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              Quantitative profiling method for oxylipin metabolome by liquid chromatography electrospray ionization tandem mass spectrometry.

              Cyclooxygenase, lipoxygenase, and epoxygenase derived oxylipins, especially eicosanoids, play important roles in many physiological processes. Assessment of oxidized fatty acid levels is important for understanding their homeostatic and pathophysiological roles. Most reported methods examine these pathways in isolation. The work described here employed a solid phase extraction-liquid chromatography-electrospray ionization MS/MS (SPE-LC-ESI MS/MS) method to monitor these metabolites. In 21 min, 39 oxylipins were quantified along with eight corresponding internal standards. The limits of quantification were between 0.07 and 32 pg (20 pM-10 nM). Finally, the validated method was used to evaluate oxylipin profiles in lipopolysaccharide-exposed mice, an established septic inflammatory model. The method described here offers a useful tool for the evaluation of complex regulatory oxylipin responses in in vitro or in vivo studies.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                October 2014
                05 September 2014
                : 51
                : 4
                : 269-282
                aDivision of Nephrology and Hypertension and bDepartment of Pharmacology and Toxicology, University of Utah, and cMedical Service, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah, and dDepartment of Entomology and Comprehensive Cancer Center, University of California, Davis, Calif., USA
                Author notes
                *Dr. Alfred K. Cheung, Division of Nephrology and Hypertension, University of Utah, 85 North Medical Drive East, Salt Lake City, UT 84112 (USA), E-Mail
                365251 PMC4235611 J Vasc Res 2014;51:269-282
                © 2014 S. Karger AG, Basel

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                Page count
                Figures: 9, Tables: 1, Pages: 14
                Research Paper


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