Two pharmacological epoxyeicosatrienoic acid-enhancing therapies are effectively antihypertensive and reduce the severity of ischemic arrhythmias in rats with angiotensin II-dependent hypertension

Červenka, Luděk; Husková, Zuzana; Kopkan, Libor; Kikerlová, Soňa; Sedláková, Lenka; Vaňourková, Zdeňka; Alánová, Petra; Kolář, František; Hammock, Bruce D.; Hwang, Sung Hee; Imig, John D.; Falck, John R.; Sadowski, Janusz; Kompanowska-Jezierska, Elżbieta; Neckář, Jan

doi:10.1097/hjh.0000000000001708

Cited by 27 publications

(31 citation statements)

References 90 publications

(243 reference statements)

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“…Furthermore, we have examined the association of R287Q variant with the enzyme activity of soluble epoxide hydrolase and found a significant lower level of the 11,12-DHET in the mutation group than in the wild-type group. Our findings are biologically plausible, as soluble epoxide hydrolase is an enzyme responsible for rapid conversion of cytochrome P450 arachidonic acid epoxygenase metabolites, to inactive or less active DHETs [23,24]. For practical reasons, our findings represent a novel approach to understanding molecular mechanisms involved in the pathogenesis of hypertension and may help target therapies according to the genotypes of R287Q variant for patients with primary hypertension to optimize prevention strategies.…”

Section: Discussionmentioning

confidence: 72%

Association of Epoxide Hydrolase 2 Gene Arg287Gln with the Risk for Primary Hypertension in Chinese

Zhao

et al. 2020

International Journal of Hypertension

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Background. Epoxide hydrolase 2 (EPHX2) gene coding for soluble epoxide hydrolase is a potential candidate in the pathogenesis of hypertension. Objectives. We aimed to assess the association of a missense mutation, R287Q, in EPHX2 gene with primary hypertension risk and examine its association with enzyme activity of soluble epoxide hydrolase. Methods. This study involved 782 patients with primary hypertension and 458 healthy controls. Genotyping was done using TaqMan technique. Activity of soluble epoxide hydrolase fusion proteins was evaluated by the conversion of 11,12-EET to corresponding 11,12-DHET using ELISA kit. Results. After taking carriers of R287Q variant GG genotype as a reference, those with GA genotype had a significantly reduced risk of hypertension (adjusted odds ratio: 0.72, 95% confidence interval: 0.56 to 0.93, P = 0.013). Five significant risk factors were identified, including age, body mass index, total cholesterol, homocysteine, and R287Q variant. These five risk factors for hypertension were represented in a nomogram, with a descent prediction accuracy (C-index: 0.833, P<0.001). Enzyme activity of soluble epoxide hydrolase was significantly lower in the R287Q group than in the wild type group. Conclusions. We provide evidence that R287Q mutation in EPHX2 gene was associated with reduced risk of primary hypertension and low activity of soluble epoxide hydrolase.

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Section: Discussionmentioning

confidence: 72%

Association of Epoxide Hydrolase 2 Gene Arg287Gln with the Risk for Primary Hypertension in Chinese

Zhao

et al. 2020

International Journal of Hypertension

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“…Previous experimental studies demonstrated that chronic treatment with sEH inhibitors results in increased EET levels and diminishes the development of LV hypertrophy due to pressure or volume overload [ 19 , 37 – 42 ]. We reported that two-week treatment with orally active EET-analogs attenuate hypertension-induced organ injury by reducing inflammation, oxidative stress, and endoplasmic reticulum stress [ 15 , 16 ].…”

Section: Discussionmentioning

confidence: 99%

Epoxyeicosatrienoic acid analog EET-B attenuates post-myocardial infarction remodeling in spontaneously hypertensive rats

et al. 2019

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Epoxyeicosatrienoic acids (EETs) and their synthetic analogs have cardiovascular protective effects. Here, we investigated the action of a novel EET analog EET-B on the progression of post-myocardial infarction (MI) heart failure in spontaneously hypertensive rats (SHR). Adult male SHR were divided into vehicle- and EET-B (10 mg/kg/day; p.o., 9 weeks)-treated groups. After 2 weeks of treatment, rats were subjected to 30-min left coronary artery occlusion or sham operation. Systolic blood pressure (SBP) and echocardiography (ECHO) measurements were performed at the beginning of study, 4 days before, and 7 weeks after MI. At the end of the study, tissue samples were collected for histological and biochemical analyses. We demonstrated that EET-B treatment did not affect blood pressure and cardiac parameters in SHR prior to MI. Fractional shortening (FS) was decreased to 18.4 ± 1.0% in vehicle-treated MI rats compared with corresponding sham (30.6 ± 1.0%) 7 weeks following MI induction. In infarcted SHR hearts, EET-B treatment improved FS (23.7 ± 0.7%), markedly increased heme oxygenase-1 (HO-1) immunopositivity in cardiomyocytes and reduced cardiac inflammation and fibrosis (by 13 and 19%, respectively). In conclusion, these findings suggest that EET analog EET-B has beneficial therapeutic actions to reduce cardiac remodeling in SHR subjected to MI.

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“…myocardial infarction was induced by 60-min ligation of the left coronary artery 1–2 mm distal to the left atrial appendage. In our hands, this procedure inducing irreversible ischemia affects around 40% of LV myocardium in Sprague-Dawley rats [ 60 ]. Sham-operated rats ( n = 6) underwent chest surgery without the occlusion.…”

Section: Methodsmentioning

confidence: 99%

“…In the HF group ( n = 9), it was first separated the fibrotic infarcted zone from the remote/non-infarcted zone of the LV which was taken for analyses. In our recent studies using similar protocols, the mean infarcted zone occupied between 30% and 40% of failing LV midwall circumference [ 8 , 45 , 60 ].…”

Section: Methodsmentioning

confidence: 99%

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Programmed Cell Death in the Left and Right Ventricle of the Late Phase of Post-Infarction Heart Failure

Lichý

Szobi

Hrdlička

et al. 2020

IJMS

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While necroptosis has been shown to contribute to the pathogenesis of post-infarction heart failure (HF), the role of autophagy remains unclear. Likewise, linkage between these two cell death modalities has not been sufficiently investigated. HF was induced by 60-min left coronary occlusion in adult Wistar rats and heart function was assessed 6 weeks later followed by immunoblotting analysis of necroptotic and autophagic proteins in both the left (LV) and right ventricle (RV). HF had no effect on RIP1 and RIP3 expression. PhosphoSer229-RIP3, acting as a pro-necroptotic signal, was increased in LV while deceased in RV of failing hearts. Total MLKL was elevated in RV only. Decrease in pSer555-ULK1, increase in pSer473-Akt and no significant elevation in beclin-1 and LC3-II/I ratio indicated rather a lowered rate of autophagy in LV. No beclin-1 upregulation and decreased LC3 processing also suggested the inhibition of both autophagosome formation and maturation in RV of failing hearts. In contrast, p89 PARP1 fragment, a marker of executed apoptosis, was increased in RV only. This is the first study showing a different signaling in ventricles of the late phase of post-infarction HF, highlighting necroptosis itself rather than its linkage with autophagy in LV, and apoptosis in RV.

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Two pharmacological epoxyeicosatrienoic acid-enhancing therapies are effectively antihypertensive and reduce the severity of ischemic arrhythmias in rats with angiotensin II-dependent hypertension

Cited by 27 publications

References 90 publications

Association of Epoxide Hydrolase 2 Gene Arg287Gln with the Risk for Primary Hypertension in Chinese

Association of Epoxide Hydrolase 2 Gene Arg287Gln with the Risk for Primary Hypertension in Chinese

Epoxyeicosatrienoic acid analog EET-B attenuates post-myocardial infarction remodeling in spontaneously hypertensive rats

Programmed Cell Death in the Left and Right Ventricle of the Late Phase of Post-Infarction Heart Failure

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