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. 2015 Dec 15;309(12):L1478-86.
doi: 10.1152/ajplung.00208.2015. Epub 2015 Oct 23.

EET-dependent potentiation of pulmonary arterial pressure: sex-different regulation of soluble epoxide hydrolase

Sharath Kandhi  1 , Jun Qin  2 , Ghezal Froogh  1 , Houli Jiang  3 , Meng Luo  4 , Michael S Wolin  1 , An Huang  1 , Dong Sun  5
Affiliations

EET-dependent potentiation of pulmonary arterial pressure: sex-different regulation of soluble epoxide hydrolase

Sharath Kandhi et al. Am J Physiol Lung Cell Mol Physiol. .

Abstract

We tested the hypothesis that suppression of epoxyeicosatrienoic acid (EET) metabolism via genetic knockout of the gene for soluble epoxide hydrolase (sEH-KO), or female-specific downregulation of sEH expression, plays a role in the potentiation of pulmonary hypertension. We used male (M) and female (F) wild-type (WT) and sEH-KO mice; the latter have high pulmonary EETs. Right ventricular systolic pressure (RVSP) and mean arterial blood pressure (MABP) in control and in response to in vivo administration of U46619 (thromboxane analog), 14,15-EET, and 14,15-EEZE [14,15-epoxyeicosa-5(z)-enoic acid; antagonist of EETs] were recorded. Basal RVSP was comparable among all groups of mice, whereas MABP was significantly lower in F-WT than M-WT mice and further reduced predominantly in F-KO compared with M-KO mice. U46619 dose dependently increased RVSP and MABP in all groups of mice. The increase in RVSP was significantly greater and coincided with smaller increases in MABP in M-KO and F-WT mice compared with M-WT mice. In F-KO mice, the elevation of RVSP by U46619 was even higher than in M-KO and F-WT mice, associated with the least increase in MABP. 14,15-EEZE prevented the augmentation of U46619-induced elevation of RVSP in sEH-KO mice, whereas 14,15-EET-induced pulmonary vasoconstriction was comparable in all groups of mice. sEH expression in the lungs was reduced, paralleled with higher levels of EETs in F-WT compared with M-WT mice. In summary, EETs initiate pulmonary vasoconstriction but act as vasodilators systemically. High pulmonary EETs, as a function of downregulation or deletion of sEH, potentiate U46619-induced increases in RVSP in a female-susceptible manner.

Keywords: epoxyeicosatrienoic acids; pulmonary hypertension; right ventricular systolic pressure; sex difference; soluble epoxide hydrolase.

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Figures

Fig. 1.
Fig. 1.
A: original tracing for changes in right ventricular systolic pressure (RVSP) in response to U46619. B: dose-dependent increases in RVSP in response to U46619 in male (M) and female (F) wild-type (WT) mice and mice with genetic knockout (KO) of the gene for soluble epoxide hydrolase (sEH) (n = 6–9 in each group). *Curve of M-KO or F-WT mice shows significant enhancement compared with that of M-WT mice. #Curve of F-KO mice shows significant enhancement compared with those of other 3 groups of mice. C: effects of 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) on U46619 (0.2 nmol/g body wt)-induced increases in RVSP in the 4 groups of mice (n = 6–9 in each group). *Significant difference from M-KO mice. #Significant difference from F-KO mice. BW, body weight.
Fig. 2.
Fig. 2.
Total epoxyeicosatrienoic acids (EETs) (A) and the ratio of EETs to dihydroxyeicosatrienoic acids (DHETs) (B) in lungs taken from male and female WT and sEH-KO mice (n = 6–8 in each group). *Significant difference from M-WT mice. #Significant difference from F-WT mice. C: 14,15-EET-induced increases in RVSP in the 4 groups of mice (n = 5 in each group).
Fig. 3.
Fig. 3.
A: original tracing for changes in arterial blood pressure in response to U46619. B: dose-dependent increases in MABP in response to U46619 in male and female WT and sEH-KO mice (n = 6–9 in each group). *Curve of M-KO or F-WT mice shows significant reduction compared with that of M-WT mice. #Curve of F-KO mice shows significant reduction compared with those of other 3 groups of mice. C: 14,15-EET-induced reduction in MABP in the 4 groups of mice (n = 5 in each group). *Significant reduction at each dose of 14,15-EET in 4 groups of mice compared with their basal line.
Fig. 4.
Fig. 4.
Time-dependent changes in RVSP (A), mean arterial blood pressure (MABP; B), and heart rate (HR; C) of male WT mice in response to a single dose of 14,15-EET (2 ng/g body wt), injected in a volume of 20 μl within 1 and 2 min, respectively (n = 5). *Significant difference from 2-min delivery group at the same time points. D: cardiac output (CO) of male WT mice in control conditions (baseline and vehicle) and after injection of 14,15-EET (2 ng/g body wt) for 1 and 3 min, respectively (n = 5).
Fig. 5.
Fig. 5.
Protein expression of sEH (A and B), CYP2C29, and thromboxane A2 receptor (TXA2R) (C) in the lungs of male and female WT and sEH-KO mice. *Significant difference from M-WT mice (n = 3 blots from 10 mice in each group).
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