TY - JOUR
T1 - Deletion of soluble epoxide hydrolase enhances coronary reactive hyperemia in isolated mouse heart
T2 - Role of oxylipins and PPARγ
AU - Hanif, Ahmad
AU - Edin, Matthew L.
AU - Zeldin, Darryl C.
AU - Morisseau, Christophe
AU - Nayeem, Mohammed A.
PY - 2016
Y1 - 2016
N2 - 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 9,10and 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.
AB - 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 9,10and 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.
KW - Coronary reactive hyperemia
KW - Dihydroxyei-cosatrienoic acids
KW - Epoxyeicosatrienoic acids
KW - Isolated perfused heart
KW - Oxylipins
KW - Soluble epoxide hydrolase
UR - http://www.scopus.com/inward/record.url?scp=84990927946&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84990927946&partnerID=8YFLogxK
U2 - 10.1152/ajpregu.00237.2016
DO - 10.1152/ajpregu.00237.2016
M3 - Article
C2 - 27488890
AN - SCOPUS:84990927946
VL - 311
SP - R676-R688
JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
SN - 1931-857X
IS - 4
ER -