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

Kandhi, Sharath; Qin, Jun; Froogh, Ghezal; Jiang, Houli; Luo, Meng; Wolin, Michael S.; Huang, An; Sun, Dong

doi:10.1152/ajplung.00208.2015

Cited by 16 publications

(31 citation statements)

References 46 publications

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“…Consequentially, the suppression of Ephx2 mRNA is concomitantly associated with the same reduction in sEH protein levels ( Fig. 1 B and D), as we reported previously (9)(10)(11)(12)(13)20), demonstrating that regulation of sEH by estrogen is at the transcriptional level. We then indicated that DNA methylation is a crucial step in the estrogen/ER-governed regulatory process for Ephx2 expression.…”

Section: Discussionsupporting

confidence: 88%

“…Indeed, findings of estrogen-dependent suppression of sEH to increase tissue EETs in the cerebral circulation provide mechanistically based evidence for a female-favorable protection from cerebral ischemic damages (7,8). We have also provided evidence indicating that female-specific down-regulation of sEH protein expression in cardiac, pulmonary, and vascular tissues favors a greater contribution of EETs in females than males and initiates the same cardiovascular responses as those observed in male sEH-KO mice, or male mice treated with sEHIs (9)(10)(11)(12). Particularly in the microcirculation, a genetic deficiency in the Ephx2 gene or down-regulation of sEH expression elicits significantly enhanced flow/shear stress-induced vasodilation and attenuated pressure-induced vasoconstriction via an EET-dependent mechanism in the mesenteric, coronary, and skeletal muscle arterioles (9,11,13).…”

supporting

confidence: 54%

“…During this process, specific TFs interface with both methylation-direct and -indirect procedures to collectively constitute the main component of estrogen-mediated signaling through combinatorial and coordinated actions, leading to estrogen-specific physiological down-regulation of Ephx2 gene/sEH expression. Our findings uncover the molecular mechanism that provides explanations for the sexual dimorphism of sEH expression (3,19) and all of the consequences arising there, defined as a female-favorable protection against cardiac and cerebral ischemia (7)(8)(9)(10)(11)(12).…”

Section: Discussionmentioning

confidence: 80%

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Estrogen-dependent epigenetic regulation of soluble epoxide hydrolase via DNA methylation

Yang

Sun

Kandhi

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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To elucidate molecular mechanisms responsible for the sexually dimorphic phenotype of soluble epoxide hydrolase (sEH) expression, we tested the hypothesis that female-specific down-regulation of sEH expression is driven by estrogen-dependent methylation of the gene. Mesenteric arteries isolated from male, female, ovariectomized female (OV), and OV with estrogen replacement (OVE) mice, as well as the human cell line (HEK293T) were used. Methylation-specific PCR and bisulfite genomic sequencing analysis indicate significant increases in DNA/CG methylation in vessels of female and OVE compared with those of male and OV mice. The same increase in CG methylation was also observed in male vessels incubated with a physiological concentration of 17β-estradiol (17β-E) for 48 hours. All vessels that displayed increases in CG methylation were concomitantly associated with decreases in their mRNA and protein, suggesting a methylation-induced gene silencing. Transient transfection assays indicate that the activity of promoter-coding luciferase was significantly attenuated in HEK293T cells treated with 17β-E, which was prevented by additional treatment with an estrogen receptor antagonist (ICI). ChIP analysis indicates significantly reduced binding activities of transcription factors (including SP1, AP-1, and NF-κB with their binding elements located in the promoter) in vessels of female mice and human cells treated with 17β-E, responses that were prevented by ICI and Decitabine (DNA methyltransferase inhibitor), respectively. In conclusion, estrogen/estrogen receptor-dependent methylation of the promoter of gene silences sEH expression, which is involved in specific transcription factor-directed regulatory pathways.

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Section: Discussionsupporting

confidence: 88%

supporting

confidence: 54%

Section: Discussionmentioning

confidence: 80%

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Estrogen-dependent epigenetic regulation of soluble epoxide hydrolase via DNA methylation

Yang

Sun

Kandhi

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…During these processes, an EETdependent modulation of pressure-sensitive behavior was indicated for the first time that elucidates, at least in part, the mechanistic insights for EET-exerted cardioprotective properties in terms of an improvement in myocardial perfusion through a significant reduction in coronary resistance (26). Moreover, consistent with our previous findings showing a female-specific downregulation of sEH in arteries of skeletal muscle and mesentery (29), as well as in the pulmonary circulation (22) to potentiate the bioactivity of EETs, the present study indicates a female-favorable attenuation of myogenic constriction, as a function of suppression of sEH expression in the coronary circulation revealing, from a physiological point of view, the female-specific regulation that possesses universally based characteristics.…”

Section: Discussionsupporting

confidence: 88%

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

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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.

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“…Moreover, E2 inhibits the expression/activity of soluble epoxide hydrolase (sEH), a key enzyme in EET metabolism [144]. Several studies linked low sEH activity to the pathophysiology of PAH: (1) E2-, genetic-, and pharmacologically-induced downregulation of sEH (and increased pulmonary EET) potentiates hypoxic pulmonary vasoconstriction [145][146][147]; (2) lungs from PH patients express no/little sEH; (3) hypoxia decreases the expression of sEH; and (4) when exposed to hypoxia, sEH KO mice exhibit exacerbated pulmonary vascular remodeling [147]. It seems that E2 plays a role in female-specific (physiological) downregulation of sEH, as suggested by the much higher sEH activity in male and OVX mice compared to intact female mice [148,149].…”

Section: Role Of Cyp1b1 and Estrogens In Arachidonic Acid Metabolismmentioning

confidence: 99%

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

Tofovic

Jackson

2019

IJMS

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Pulmonary arterial hypertension (PAH) is a debilitating and progressive disease that predominantly develops in women. Over the past 15 years, cumulating evidence has pointed toward dysregulated metabolism of sex hormones in animal models and patients with PAH. 17β-estradiol (E2) is metabolized at positions C2, C4, and C16, which leads to the formation of metabolites with different biological/estrogenic activity. Since the first report that 2-methoxyestradiol, a major non-estrogenic metabolite of E2, attenuates the development and progression of experimental pulmonary hypertension (PH), it has become increasingly clear that E2, E2 precursors, and E2 metabolites exhibit both protective and detrimental effects in PH. Furthermore, both experimental and clinical data suggest that E2 has divergent effects in the pulmonary vasculature versus right ventricle (estrogen paradox in PAH). The estrogen paradox is of significant clinical relevance for understanding the development, progression, and prognosis of PAH. This review updates experimental and clinical findings and provides insights into: (1) the potential impacts that pathways of estradiol metabolism (EMet) may have in PAH; (2) the beneficial and adverse effects of estrogens and their precursors/metabolites in experimental PH and human PAH; (3) the co-morbidities and pathological conditions that may alter EMet and influence the development/progression of PAH; (4) the relevance of the intracrinology of sex hormones to vascular remodeling in PAH; and (5) the advantages/disadvantages of different approaches to modulate EMet in PAH. Finally, we propose the three-tier-estrogen effects in PAH concept, which may offer reconciliation of the opposing effects of E2 in PAH and may provide a better understanding of the complex mechanisms by which EMet affects the pulmonary circulation–right ventricular interaction in PAH.

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

Cited by 16 publications

References 46 publications

Estrogen-dependent epigenetic regulation of soluble epoxide hydrolase via DNA methylation

Estrogen-dependent epigenetic regulation of soluble epoxide hydrolase via DNA methylation

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

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

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