Increased Endothelial Expression of Human Soluble Epoxide Hydrolase Negatively Modulates Coronary Reactive Hyperemia in Isolated Mouse Heart

Abstract

Coronary reactive hyperemia (RH) is impaired in hypertrophic hearts. Epoxyeicosatrienoic acids (EETs) exert cardioprotective effects in ischemia / reperfusion injury. Soluble epoxide hydrolase (sEH) is the main enzyme responsible for EETs breakdown. EETs level is decreased in transgenic mice with increased endothelial expression of sEH (Tie 2‐sEH tr). We hypothesized that the isolated mouse heart with increased expression of sEH (Tie2‐sEH Tr) exhibits decreased RH through increased hydrolysis of EETs in response to no‐flow ischemia compared to wild type (WT). Coronary flow (CF) in isolated Tie2‐sEH Tr and WT mouse heart was measured using Langendorff system. Perfused isolated heart was exposed to 15 second ischemia and RH was assessed. Following ischemia, flow repayment volume (RV) (the area under the curve and normalized to heart weight (ml/g)) was significantly decreased in Tie2‐sEH Tr compared to WT(8.7 ± 0.8 in Tie2‐sEH Tr vs. 10.7 ± 0.7 in WT, p<0.05). Moreover, Tie2‐sEH Tr exhibited significantly shorter repayment duration when compared to WT (2.4 ± 0.2 in Tie2‐sEH Tr vs. 3.3 ± 0.4 in WT, p<0.05). At the same time, left ventricular developing pressure (LVDP) and heart rate (HR) were not significantly different between the two groups (LVDP was 168.0 ± 15.1 in Tie2‐sEH Tr vs. 133.1 ± 11.6 in WT, p>0.05; HR was 397.7 ± 24.5 in Tie2‐sEH Tr vs. 387.0 ± 14.1 in WT, p>0.05)Our results demonstrate that increased endothelial expression of sEH (Tie2‐sEH Tr) decreases RH compared to WT. These data suggest that increased level of sEH could have a deleterious effect on myocardial recovery from ischemia. Supported by HL‐114559 to MAN and z01‐ES025034 to DCZ