Ephx2-gene deletion affects acetylcholine-induced relaxation in angiotensin-II infused mice: role of nitric oxide and CYP-epoxygenases

  • Ahmad Hanif
  • Matthew L. Edin
  • Darryl C. Zeldin
  • Mohammed A. NayeemEmail author


Previously, we showed that adenosine A2A receptor induces relaxation independent of NO in soluble epoxide hydrolase-null mice (Nayeem et al. in Am J Physiol Regul Integr Comp Physiol 304:R23–R32, 2013). Currently, we hypothesize that Ephx2-gene deletion affects acetylcholine (Ach)-induced relaxation which is independent of A2AAR but dependent on NO and CYP-epoxygenases. Ephx2/ aortas showed a lack of sEH (97.1%, P < 0.05) but an increase in microsomal epoxide hydrolase (mEH, 37%, P < 0.05) proteins compared to C57Bl/6 mice, and no change in CYP2C29 and CYP2J protein (P > 0.05). Ach-induced response was tested with nitro-l-arginine methyl ester (l-NAME) NO-inhibitor; 10−4 M), N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH) (CYP-epoxygenase inhibitor; 10−5 M), 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, an epoxyeicosatrienoic acid-antagonist; 10−5 M), SCH-58261 (A2AAR-antagonist; 10−6 M), and angiotensin-II (Ang-II, 10−6 M). In Ephx2/ mice, Ach-induced relaxation was not different from C57Bl/6 mice except at 10−5 M (92.75 ± 2.41 vs. 76.12 ± 3.34, P < 0.05). However, Ach-induced relaxation was inhibited with l-NAME (Ephx2/: 23.74 ± 3.76% and C57Bl/6: 11.61 ± 2.82%), MS-PPOH (Ephx2/: 48.16 ± 6.53% and C57Bl/6: 52.27 ± 7.47%), and 14,15-EEZE (Ephx2/: 44.29 ± 8.33% and C57Bl/6: 39.27 ± 7.47%) vs. non-treated (P < 0.05). But, it did not block with SCH-58261 (Ephx2/: 68.75 ± 11.41% and C57Bl/6: 66.26 ± 9.43%, P > 0.05) vs. non-treated (P > 0.05). Interestingly, Ang-II attenuates less relaxation in Ehx2−/− vs. C57Bl/6 mice (58.80 ± 7.81% vs. 45.92 ± 7.76, P < 0.05). Our data suggest that Ach-induced relaxation in Ephx2/ mice depends on NO and CYP-epoxygenases but not on A2A AR, and Ephx2-gene deletion attenuates less Ach-induced relaxation in Ang-II-infused mice.


Soluble epoxide hydrolase Acetylcholine Adenosine A2A receptor Nitric oxide CYP-epoxgenases Relaxation 



This work supported by National Institutes of Health Grant HL-114559 to M. A. Nayeem and National Institute of Environmental Health Sciences Grant Z01 ES025034 to D. C. Zeldin. In addition, we are very much thankful to Ms. Brandy J. Wilmoth, B.S., RVT (Biology Technician) for performing tissue bath experiments and thankful to Amanda G. Ammer, PhD. (Research Assistant Professor), Department of Microbiology, Immunology and Cell Biology for editing and correcting this manuscript.

Author contributions

MAN: conception, design of research, performing experiments, analysis drafting and editing; AH: coopering in the experimentations, reading, correction, editing and input; MLE: reading, correction, editing and input and DCZ: advising, reading, correction, editing, provide transgenic mice and input.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest, financial or otherwise.


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Authors and Affiliations

  1. 1.Pharmaceutical Sciences, School of PharmacyWest Virginia UniversityMorgantownUSA
  2. 2.Division of Intramural ResearchNIEHS/NIHResearch Triangle ParkUSA
  3. 3.Department of Pharmaceutical Sciences, Health Science Center–School of PharmacyWest Virginia UniversityMorgantownUSA

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