Inhibition of soluble epoxide hydrolase increases coronary perfusion in mice

Qin, Jun; Sun, Dong; Jiang, Houli; Kandhi, Sharath; Froogh, Ghezal; Hwang, Sung Hee; Hammock, Bruce D.; Wolin, Michael S.; Thompson, Carl I.; Hintze, Thomas H.; Huang, An

doi:10.14814/phy2.12427

Cited by 14 publications

(22 citation statements)

References 46 publications

(103 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This finding implies that the female sex may possess a specific regulatory mechanism that mimics the Ephx2 gene deletion. Also, an unchanged 5,6-EET/DHET in response to disruption of the Ephx2 gene indicates that this isoform of EET is a poor substrate for sEH (36,46). Importantly, administration of 14,15-EET dose dependently elicited comparable increases in RVSP in all groups of mice (Fig.…”

Section: Changes In Rvspmentioning

confidence: 82%

“…As described in detail (36,40), esterified EETs and DHETs from tissue extracts were quantified via LC/MS/MS (AB ScieX, Qtrap 3200). Protein concentration of samples, determined by the Bradford method (Bio-Rad, Hercules, CA), was used to normalize the detected lipids, such that each regioisomer of EETs and DHETs was expressed as picograms per microgram protein.…”

Section: Lc/ms/ms-based Measurements For Lung Eets and Dhetsmentioning

confidence: 99%

See 1 more Smart Citation

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

Kandhi

Qin

Froogh

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

Self Cite

View full text Add to dashboard Cite

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. pulmonary hypertension; soluble epoxide hydrolase; epoxyeicosatrienoic acids; right ventricular systolic pressure; sex difference PULMONARY ARTERIAL HYPERTENSION (PAH) is a progressive disease with different etiologies that primarily affects small pulmonary arteries (28) and is associated with elevated pulmonary vasoconstriction, smooth muscle proliferation, endothelial dysfunction, and pulmonary remodeling (32). The two major factors that specifically contribute to the increase in pulmonary vascular resistance are vasoconstriction and vascular remodeling (9). Acute vasodilation resulting from the inhibition of Rho-kinase, an enzyme that causes sustained pulmonary vasoconstriction to generate pulmonary hypertension (33), significantly ameliorates pulmonary arterial pressure in patients with severe pulmonary hypertension (PH) (14, 17). Based on this evidence, recent studies arose to address the concern that specific roles of vasoconstriction in late stages of PH was underappreciated (39). The findings address an important issue that pulmonary artery tone and consequentially pulmonary resistance are controlled by factors released from the pulmonary vasculature. In this regard, any lung-sourced vasoconstrictors merit consideration as an endogenous trigger for PAH. For instance, endothelium-derived metabolites of arachidonic acid (AA) by lipoxygenase to ...

show abstract

Section: Changes In Rvspmentioning

confidence: 82%

Section: Lc/ms/ms-based Measurements For Lung Eets and Dhetsmentioning

confidence: 99%

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

Kandhi

Qin

Froogh

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the coronary circulation, coronary arteries are specifically exposed to a rhythmic compression generated by myocardial contraction. To this end, the pressure-sensitive mechanism becomes critically important in the regulation of coronary resistance and cardiac flow/perfusion (23,26,30,31,37). Although this pressuresensitive behavior originates from the smooth muscle layer of blood vessels that depolarizes in response to increases in pressure, and is therefore named as "myogenic response," the endothelial cells constitutively produce a variety of vasodilators such as endothelial nitric oxide (NO) that counteracts the pressure-induced vasoconstriction.…”

mentioning

confidence: 99%

Female-favorable attenuation of coronary myogenic constriction via reciprocal activations of epoxyeicosatrienoic acids and nitric oxide

Froogh

Qin

Kandhi

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid via CYP/epoxygenases, which are catabolized by soluble epoxide hydrolase (sEH) and known to possess cardioprotective properties. To date, the role of sEH in the modulation of pressure-induced myogenic response/constriction in coronary arteries, an important regulatory mechanism in the coronary circulation, and the issue as to whether the disruption of the sEH gene affects the myogenic response sex differentially have never been addressed. To this end, experiments were conducted on male (M) and female (F) wild-type (WT) and sEH-knockout (KO) mice. Pressure-diameter relationships were assessed in isolated and cannulated coronary arteries. All vessels constricted in response to increases in intraluminal pressure from 60 to 120 mmHg. Myogenic vasoconstriction was significantly attenuated, expressed as an upward shift in the pressure-diameter curve of vessels, associated with higher cardiac EETs in M-KO, F-WT, and F-KO mice compared with M-WT controls. Blockade of EETs via exposure of vessels to 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) prevented the attenuated myogenic constriction in sEH-KO mice. In the presence of 14,15-EEZE, pressure-diameter curves of females presented an upward shift from those of males, exhibiting a sex-different phenotype. Additional administration of Nω-nitro-l-arginine methyl ester eliminated the sex difference in myogenic responses, leading to four overlapped pressure-diameter curves. Cardiac sEH was downregulated in F-WT compared with M-WT mice, whereas expression of endothelial nitric oxide synthase and CYP4A (20-HETE synthase) was comparable among all groups. In summary, in combination with NO, the increased EET bioavailability as a function of genetic deletion and/or downregulation of sEH accounts for the female-favorable attenuation of pressure-induced vasoconstriction.

show abstract

“…These sums provide an index of the overall CYP450-mediated epoxygenation toward each of the fatty acids ( 6,16 ). We also secondarily assessed each MEFA regioisomer derived from the same PUFA, as well as the epoxide:diol ratio for each MEFA, an index that is inversely correlated with soluble epoxide hydrolase activity and has been suggested to be a proxy for the enzyme activity in vivo ( 17,18 ). We evaluated this ratio in our study because n-3 PUFA supplementation has been shown in animal studies to change soluble epoxide hydrolase expression ( 19 ).…”

Section: Discussionmentioning

confidence: 99%

“…This enzyme is therefore a potential therapeutic target, and the manipulation of its expression or activity (and therefore the epoxide:diol ratio) in animal studies infl uences infl ammation and other physiological parameters (16)(17)(18).…”

Section: Discussionmentioning

confidence: 99%

Effect of fish oil on monoepoxides derived from fatty acids during cardiac surgery

Akintoye

Hou

et al. 2016

Journal of Lipid Research

View full text Add to dashboard Cite

Growing evidence highlights the importance of endogenous anti-infl ammatory mediators in appropriate modulation of infl ammatory responses and suggests that breakdowns in the metabolism of these highly bioactive molecules may underlie disease development ( 1-5 ). One key class of these metabolic regulators is the monoepoxides derived from polyunsaturated fatty acids (MEFAs), synthesized from long-chain omega-3 (n-3) and omega-6 (n-6) PUFAs by cytochrome P450 (CYP450) enzymes ( Fig. 1 ) ( 6 ). Once synthesized, MEFAs can be incorporated into membrane phospholipids or further metabolized by soluble epoxide hydrolase to their less active corresponding diols. In experimental and animal models, MEFAs have potent anti-infl ammatory and vascular protective properties, suggesting potential for development of MEFA-based therapies to target infl ammatory disorders and cardiovascular diseases ( 3, 5, 7 ). However, MEFAs have rarely been measured in humans, and important questions remain regarding their usual physiological concentrations, the interrelationship between different MEFAs derived from different classes of PUFAs, and if and by how much endogenous levels of Abstract Our objective was to assess the dynamics of monoepoxides derived from polyunsaturated fatty acids (MEFAs), and their response to n-3 PUFA supplementation, in the setting of acute tissue injury and infl ammation (cardiac surgery) in humans. Patients (479) undergoing cardiac surgery in three countries were randomized to perioperative fi sh oil (EPA + DHA; 8-10 g over 2-5 days preoperatively, then 2 g/day postoperatively) or placebo (olive oil). Plasma MEFAs derived from n-3 and n-6 PUFAs were measured 2 days postoperatively. Based on serial measures in a subset of the placebo group, levels of all MEFAs declined substantially following surgery (at postoperative day 2), with declines ranging from 37% to 63% ( P < 0.05 each). Compared with placebo at postoperative day 2, levels of EPA-and DHA-derived MEFAs were 40% and 18% higher, respectively ( P Յ 0.004). The n-3 PUFA supplementation did not signifi cantly alter the decline in n-6 PUFA-derived MEFAs. Both enrollment level and changes in plasma phospholipid EPA and DHA were associated with their respective MEFAs at postoperative day 2 ( P < 0.001). Under the acute stress of cardiac surgery, n-3 PUFA supplementation signifi cantly ameliorated the reduction in postoperative n-3 MEFAs, but not n-6 MEFAs, and the degree of increase in n-3 MEFAs related positively to the circulating level of their n-3 PUFA precursors . -Akintoye, E., J.

show abstract

Inhibition of soluble epoxide hydrolase increases coronary perfusion in mice

Cited by 14 publications

References 46 publications

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

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

Female-favorable attenuation of coronary myogenic constriction via reciprocal activations of epoxyeicosatrienoic acids and nitric oxide

Effect of fish oil on monoepoxides derived from fatty acids during cardiac surgery

Contact Info

Product

Resources

About