1. Deletion of soluble epoxide hydrolase enhances coronary reactive hyperemia in isolated mouse heart: role of oxylipins and PPARγ
- Author
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Ahmad Hanif, Darryl C. Zeldin, Matthew L. Edin, Christophe Morisseau, and Mohammed A. Nayeem
- Subjects
Male ,0301 basic medicine ,Epoxide hydrolase 2 ,medicine.medical_specialty ,Cardiovascular and Renal Integration ,Physiology ,Peroxisome proliferator-activated receptor ,Hyperemia ,In Vitro Techniques ,Mice ,03 medical and health sciences ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Oxylipins ,Receptor ,Reactive hyperemia ,Epoxide Hydrolases ,Mice, Knockout ,chemistry.chemical_classification ,Oxylipin ,Peroxisome ,medicine.disease ,Coronary Vessels ,PPAR gamma ,030104 developmental biology ,Endocrinology ,chemistry ,cardiovascular system ,Female ,Rosiglitazone ,Reperfusion injury ,medicine.drug - Abstract
The relationship between soluble epoxide hydrolase (sEH) and coronary reactive hyperemia (CRH) response to a brief ischemic insult is not known. Epoxyeicosatrienoic acids (EETs) exert cardioprotective effects in ischemia/reperfusion injury. sEH converts EETs into dihydroxyeicosatrienoic-acids (DHETs). Therefore, we hypothesized that knocking out sEH enhances CRH through modulation of oxylipin profiles, including an increase in EET/DHET ratio. Compared with sEH+/+, sEH−/− mice showed enhanced CRH, including greater repayment volume (RV; 28% higher, P < 0.001) and repayment/debt ratio (32% higher, P < 0.001). Oxylipins from the heart perfusates were analyzed by LC-MS/MS. The 14,15-EET/14,15-DHET ratio was 3.7-fold higher at baseline ( P < 0.001) and 5.6-fold higher post-ischemia ( P < 0.001) in sEH−/− compared with sEH+/+ mice. Likewise, the baseline 9,10- and 12,13-EpOME/DiHOME ratios were 3.2-fold ( P < 0.01) and 3.7-fold ( P < 0.001) higher, respectively in sEH−/− compared with sEH+/+ mice. 13-HODE was also significantly increased at baseline by 71% ( P < 0.01) in sEH−/− vs. sEH+/+ mice. Levels of 5-, 11-, 12-, and 15-hydroxyeicosatetraenoic acids were not significantly different between the two strains ( P > 0.05), but were decreased postischemia in both groups ( P = 0.02, P = 0.04, P = 0.05, P = 0.03, respectively). Modulation of CRH by peroxisome proliferator-activated receptor gamma (PPARγ) was demonstrated using a PPARγ-antagonist (T0070907), which reduced repayment volume by 25% in sEH+/+ ( P < 0.001) and 33% in sEH−/− mice ( P < 0.01), and a PPARγ-agonist (rosiglitazone), which increased repayment volume by 37% in both sEH+/+ ( P = 0.04) and sEH−/− mice ( P = 0.04). l-NAME attenuated CRH in both sEH−/− and sEH+/+. These data demonstrate that genetic deletion of sEH resulted in an altered oxylipin profile, which may have led to an enhanced CRH response. more...
- Published
- 2016
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