Soluble epoxide hydrolase-dependent regulation of myogenic response and blood pressure

Sun, Dong; Cuevas, Azita J.; Gotlinger, Katherine; Hwang, Sung Hee; Hammock, Bruce D.; Schwartzman, Michal Laniado; Huang, An

doi:10.1152/ajpheart.00920.2013

Cited by 34 publications

(40 citation statements)

References 57 publications

(70 reference statements)

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“…The recognition that the female sex and/or estrogen favors the contribution of EETs has been documented (38). We also demonstrated that, in resistance arteries, actions of EETs become discernable when EET degradation is compromised (40). Thus, via genetic disruption of the sEH gene to increase intracellular EET levels and prolong their vascular actions, we were able to evaluate the pathophysiological significance of sEH/EETs in the regulation of pulmonary and systemic circulations, as a function of sex.…”

Section: Discussionmentioning

confidence: 63%

“…As described previously (40), cryorecovered heterozygous (Ephx2 ϩ/Ϫ , B6.129X-Ephx2tm1Gonz/J) and WT (Ephx2 ϩ/ϩ ) mice were received from the Jackson Laboratory (Bar Harbor, ME) and the homozygous (Ephx2 Ϫ/Ϫ ) mice were bred in the Department of Comparative Medicine, New York Medical College.…”

Section: Twelve-to 15-wk-old Male (M) and Female (F) Ephx2mentioning

confidence: 99%

“…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%

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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

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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 ...

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Section: Discussionmentioning

confidence: 63%

Section: Twelve-to 15-wk-old Male (M) and Female (F) Ephx2mentioning

confidence: 99%

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

confidence: 99%

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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

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“…16 These observations likely reflect EET attenuation of vascular myogenic responses in resistance arterioles, as shown in sEH knockout mice or with sEH inhibitors. 17 The correlation between DHET and plasma aldosterone in SR could reflect parallel dichotomization of both parameters by changes in salt balance (inhibition by salt loading and stimulation by salt depletion). However, it was also present during the periods of small variance of aldosterone levels (baseline and high-salt days).…”

Section: Discussionmentioning

confidence: 99%

Two Pools of Epoxyeicosatrienoic Acids in Humans

Elijovich

Milne

Brown³

et al. 2018

Hypertension

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E poxyeicosatrienoic acids (EETs) are products of epoxygenation of arachidonic acid. They participate in cardiovascular regulation via vasodilator and natriuretic effects. Research on their actions used urine or plasma measurements of their 4 active regioisomers (5,8,11,and 14, and their relatively inactive derivatives, the dihydroxyeicosatrienoic acids [DHETs]. The latter are produced by enzymatic (soluble epoxide hydrolase [sEH]) or nonenzymatic (eg, pH, oxidative stress) degradation.Previous studies in animals suggested that urine and plasma EETs may reflect 2 distinct pools with different functions. The volume of distribution of intravenous radiolabeled 14,15-EET in dogs approximates their plasma volume, and no radioactivity can be detected in their urine.1 Plasma EET responses to regulatory PPARα (peroxisome proliferatoractivated receptor α) ligands in mice run parallel to Cyp2c epoxygenase expression and EET biosynthesis in the liver. These studies suggest that plasma EETs reflect a systemic, not a renal pool. Conversely, increased renal EET content produced by dopamine agonists in mice is not associated with changes in plasma EETs,3 indicating that the renal EET pool might be better reflected by urine measurements. Our first aim was to assess whether these putative pools could be uncovered by studying clinical and biochemical correlates of urine and plasma EETs in normal volunteers; that is, normotensive, saltresistant (SR) subjects, during salt loading and depletion.EETs may play a role in salt sensitivity of blood pressure (BP). Salt stimulates renal microsomal biosynthesis of EETs in normal Sprague Dawley 4 and Dahl-R rats, 5 whereas this response is absent in the salt-sensitive (SS) Dahl-S strain, leading to hypertension with reduced renal expression of the epoxygenase CYP2C23 and urine excretion of EETs. 5 In SR rats, the epoxygenase inhibitor clotrimazole decreases urinary EETs and reproduces SS hypertension.5 Cyp4a10 knockout mice, which have reduced renal epoxygenase (Cyp2c44) activity, 6 and the Cyp2c44 knockout, 7 have diminished urine EETs and amiloride-sensitive hypertension. This is associated with decreased inactivating threonine phosphorylation of γENaC (epithelial sodium channel), 7 which is reversible by the PPARα ligands that stimulate epoxygenases.6 Our second aim was to investigate whether SS subjects exhibit differences in urine or plasma EETs levels or in their responses to changes in salt balance or in their clinical or biochemical correlates compared with SR. To avoid confounding effects of established hypertension, we performed these studies in normotensive volunteers.Abstract-We measured epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) in 21 normotensive subjects classified as salt resistant (13) or salt sensitive (8) with an inpatient protocol of salt loading (460 mEq Na + /24 hours, HiNa) and depletion (10 mEq Na + /24 hours+furosemide 40 mg×3, LoNa). No urine EETs were detected; hence, enzyme linked innumosorbent assay 14,15-DHETs (dihydroxyeicosatrie...

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“…The efficacy of endothelial removal and the intact vasomotor function of smooth muscle were validated by the loss of arteriolar dilation to the endothelium‐dependent vasodilator acetylcholine (10 −6 mol/L) and maintained dilation to the nitric oxide (NO) donor (NONOate, 10 −6 mol/L), respectively (Table). 9 …”

Section: Resultsmentioning

confidence: 99%

Extravascular Blood Augments Myogenic Constriction of Cerebral Arterioles: Implications for Hemorrhage‐Induced Vasospasm

Deng

Kandhi

Zhang

et al. 2018

JAHA

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BackgroundSubarachnoid hemorrhage is a serious clinical condition that impairs local cerebral blood flow perfusion and consequently initiates neuronal dysfunction. Pressure‐sensitive myogenic vasomotor regulation is an important mechanism involved in the regulation of cerebral blood flow. We hypothesized that extravascular hemolyzed blood enhances arteriolar myogenic constriction, which in vivo may contribute to the reduction of local cerebral blood flow after subarachnoid hemorrhage.Methods and ResultsArterioles isolated from the middle cerebral artery (MCA arterioles) of mice were cannulated in a perfusion chamber. Arteriolar diameters in response to step increases in intraluminal pressure (20–120 mm Hg) were measured in various experimental conditions. In response to increases in intraluminal pressure, all MCA arterioles exhibited myogenic vasoconstrictions. Compared with controls, the pressure‐induced constriction was significantly enhanced in arterioles (in vitro) exposed to extravascular hemolyzed blood or different concentrations of extracellular erythrocyte lysate (1%, 10%, and 20%) for different exposure durations (1–6 hours). The magnitude of enhancement was proportional to the lysate concentration and exposure duration. In in vivo experiments, 10 μL of autologous blood lysate were injected into the mouse subarachnoid space on the surface of the left MCA. Two hours later, MCA arterioles were isolated and left MCA arterioles displayed enhanced myogenic responses compared with the right MCA. The enhanced myogenic response was prevented by scavenge of superoxide in both in vitro and in vivo experiments.ConclusionsExtravascular hemolyzed blood, perhaps by promoting vascular production of superoxide, augments myogenic constriction of cerebral arterioles, which plays a crucial role in the subarachnoid hemorrhage–induced cerebral ischemia.

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Soluble epoxide hydrolase-dependent regulation of myogenic response and blood pressure

Cited by 34 publications

References 57 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

Two Pools of Epoxyeicosatrienoic Acids in Humans

Extravascular Blood Augments Myogenic Constriction of Cerebral Arterioles: Implications for Hemorrhage‐Induced Vasospasm

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