EET-dependent potentiation of pulmonary arterial pressure: sex-different regulation of soluble epoxide hydrolase.
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.
Department of Physiology, New York Medical College, Valhalla, New York;
Sharath
S
Kandhi
Department of Physiology, New York Medical College, Valhalla, New York; Department of Surgery, Renji Hospital, Shanghai Jiaotong University, School of Medicine, People's Republic of China; and.
Jun
J
Qin
Department of Physiology, New York Medical College, Valhalla, New York;
Ghezal
G
Froogh
Department of Pharmacology, New York Medical College, Valhalla, New York;
Houli
H
Jiang
Department of Surgery, Renji Hospital, Shanghai Jiaotong University, School of Medicine, People's Republic of China; and Shanghai 9th Hospital, Shanghai Jiaotong University, School of Medicine, People's Republic of China.
Meng
M
Luo
Department of Physiology, New York Medical College, Valhalla, New York;
Michael S
MS
Wolin
Department of Physiology, New York Medical College, Valhalla, New York;
An
A
Huang
Department of Physiology, New York Medical College, Valhalla, New York; dong_sun@nymc.edu.
Dong
D
Sun
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects* / Q000502:physiology*; D004851:Epoxide Hydrolases / Q000378:metabolism*; D005260:Female; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology*; D012727:Sex Characteristics; D014661:Vasoconstriction / Q000187:drug effects
C494022:14,15-eicosa-5-enoic acid; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid
epoxyeicosatrienoic acids; pulmonary hypertension; right ventricular systolic pressure; sex difference; soluble epoxide hydrolase