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Vascular endothelial over-expression of soluble epoxide hydrolase (Tie2-sEH) enhances adenosine A1 receptor-dependent contraction in mouse mesenteric arteries: role of ATP-sensitive K+ channels

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Abstract

Soluble epoxide hydrolase (sEH) converts epoxyeicosatrienoic acids that are endothelium-derived hyperpolarizing factors into less active dihydroxyeicosatrienoic acids. Previously, we reported a decrease in adenosine A1 receptor (A1AR) protein levels in sEH knockout (sEH−/−) and an increase in sEH and A1AR protein levels in A2AAR−/− mice. Additionally, KATP channels are involved in adenosine receptor (AR)-dependent vascular relaxation. Thus, we hypothesize that a potential relationship may exist among sEH over-expression, A1AR upregulation, inactivation of KATP channels, and increased in vascular tone. We performed DMT myograph muscle tension measurements and western blot analysis in isolated mouse mesenteric arteries (MAs) from wild-type (WT) and endothelial over-expression of sEH (Tie2-sEH Tr) mice. Our data revealed that NECA (a non-selective adenosine receptors agonist)-induced relaxation was significantly reduced in Tie2-sEH Tr mice, and CCPA (A1AR agonist)-induced contraction was increased in Tie2-sEH Tr mice. A1AR-dependent contraction in Tie2-sEH Tr mice was significantly attenuated by pharmacological inhibition of CYP4A (HET0016, 10 µM), PKCα (GO6976, 1 µM), and ERK1/2 (PD58059, 1 µM). Our western blot analysis revealed significantly higher basal protein expression of CYP4A, A1AR, and reduced p-ERK in MAs of Tie2-sEH Tr mice. Notably, pinacidil (KATP channel opener)-induced relaxation was also significantly reduced in MAs of Tie2-sEH Tr mice. Furthermore, KATP channel-dependent relaxation in MAs was enhanced by inhibition of PKCα and ERK1/2 in WT but not Tie2-sEH Tr mice. In conclusion, our data suggest that over-expression of sEH enhances A1AR-dependent contraction and reduces KATP channel-dependent relaxation in MAs. These results suggest a possible interaction between sEH, A1AR, and KATP channels in regulating vascular tone.

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Acknowledgments

This study was supported by HL-114559 (to Mohammed Nayeem, PhD.) and z01-ES025034 (Darryl Zeldin, M.D.). The authors would like to thank Jamal Mustafa, PhD. for allowing Vishal Yadav, PhD. (Postdoctoral Fellow in his lab) to work in this project. The authors appreciate the help provided by Sherry Xie for western blot experiment.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, College of Medicine, West Virginia University, Morgantown, WV, USA

    Vishal R. Yadav

  2. Department of Pharmaceutical Sciences, Center for Basic and Translational Stroke Research, Health Science Center-North, School of Pharmacy, West Virginia University, Biomedical Research Building, 2nd floor, Room # 220, 1 Medical Center Drive, PO Box 9530, Morgantown, WV, 26506-9530, USA

    Ka L. Hong & Mohammed A. Nayeem

  3. Division of Intramural Research, NIEHS/NIH, Research Triangle Park, NC, USA

    Darryl C. Zeldin

Authors
  1. Vishal R. Yadav
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  2. Ka L. Hong
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  4. Mohammed A. Nayeem
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Correspondence to Mohammed A. Nayeem.

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Yadav, V.R., Hong, K.L., Zeldin, D.C. et al. Vascular endothelial over-expression of soluble epoxide hydrolase (Tie2-sEH) enhances adenosine A1 receptor-dependent contraction in mouse mesenteric arteries: role of ATP-sensitive K+ channels. Mol Cell Biochem 422, 197–206 (2016). https://doi.org/10.1007/s11010-016-2821-z

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