Increased Endothelial Expression of Human Cytochrome P450 Epoxygenase 2J2 Positively Modulates Coronary Reactive Hyperemia in Isolated Mouse Heart

Abstract

Impaired coronary reactive hyperemia (RH) is associated with increased cardiovascular disease. Epoxyeicosatrienoic acids (EETs) exert cardioprotective effects in ischemia / reperfusion injury. Cytochrome P450 epoxygenase 2J2 partly generates EETs from arachidonic acid. EETs level is increased in mice with increased endothelial expression of CYP2J2 (Tie2‐CYP2J2 tr). We hypothesized that the isolated heart from Tie2‐CYP2J2 tr mouse exhibits increased RH through increased generation of EETs in response to no‐flow ischemia compared to wild type (WT). Coronary flow (CF) in isolated Tie2‐CYP2J2 Tr and WTmouse heart was measured using Langendorff system. Perfused heart was exposed to 15 second ischemia and RH was assessed. Flow repayment volume (RV) (the area under the curve normalized to heart weight (ml/g)) was significantly increased in Tie2‐CYP2J2 Tr compared to WT(9.8 ± 0.9 in Tie2‐CYP2J2 Tr vs. 6.4 ± 0.5 in WT, p<0.05). Tie2‐CYP2J2 Tr exhibited significantly longer repayment duration when compared to WT (2.5 ± 0.4 in Tie2‐CYP2J2 Tr vs. 1.7 ± 0.2 in WT, p<0.05). MS‐PPOH (CYP epoxygenase inhibitor, 1.0 mM) decreased RH in Tie2‐CYP2J2 Tr (7.96 ± 0.41 with MS‐PPOH vs. 9.8 ± 0.9 without MS‐PPOH , p<0.05), but not in WT. Our results demonstrate that increased endothelial expression of CYP2J2 increases RH compared to WT; also, MS‐PPOH decreases RH in Tie2‐CYP2J2 but not in WT. These data suggest that increased level of CYP2J2 could have a beneficial effect on myocardial recovery from short ischemia. Supported by HL‐114559 to MAN, z01‐ES025034 to DCZ and GM31278 to JRF