Soluble Epoxide Hydrolase Inhibitors Regulate Ischemic Arrhythmia by Targeting MicroRNA-1

Background: Soluble epoxide hydrolase inhibitors (sEHis) inhibit the degradation of epoxyeicosatrienoic acids (EETs) in cells, and EETs have antiarrhythmic effects. Our previous experiments confirmed that t-AUCB, a preparation of sEHis, inhibited ischemic arrhythmia by negatively regulating microRNA-1 (miR-1), but its specific mechanism remained unclear.Aim: This study aimed to examine the role of serum response factor (SRF) and the PI3K/Akt/GSK3β pathway in t-AUCB-mediated regulation of miR-1 and the interaction between them.Methods/Results: We used SRF small interfering RNA (siSRF), SRF small hairpin (shSRF) RNA sequence adenovirus, PI3K/Akt/GSK3β pathway inhibitors, t-AUCB, and 14,15-EEZE (a preparation of EETs antagonists) to treat mouse cardiomyocytes overexpressing miR-1 and mice with myocardial infarction (MI). We found that silencing SRF attenuated the effects on miR-1 and its target genes KCNJ2 and GJA1 in the presence of t-AUCB, and inhibition of the PI3K/Akt/GSK3β pathway antagonized the effects of t-AUCB on miR-1, KCNJ2, and GJA1, which were associated with PI3Kα, Akt, and Gsk3β but not PI3Kβ or PI3Kγ. Moreover, the PI3K/Akt/GSK3β pathway was involved in the regulation of SRF by t-AUCB, and silencing SRF inhibited the t-AUCB-induced increases in Akt and Gsk3β phosphorylation.Conclusions: Both the SRF and the PI3K/Akt/GSK3β pathway are involved in the t-AUCB-mediated regulation of miR-1, and these factors interact with each other.

A clinical perspective of soluble epoxide hydrolase inhibitors in metabolic and related cardiovascular diseases

: Epoxide hydrolase (EH) is a crucial enzyme responsible for catabolism, detoxification, and regulation of signaling molecules in various organisms including human beings. In mammals, EHs are classified according to their DNA sequence, sub-cellular location, and activity into eight major classes: soluble EH (sEH), microsomal EH (mEH), leukotriene A4 hydrolase (LTA4H), cholesterol EH (ChEH), hepoxilin EH, paternally expressed gene 1 (peg1/MEST), EH3 and EH4. The sEH, an α/β-hydrolase fold family enzyme is an emerging pharmacological target in multiple diseases namely, cardiovascular disease, neurodegenerative disease, chronic pain, fibrosis, diabetes, pulmonary diseases, and immunological disease. It exhibits prominent physiological effect that includes anti-inflammatory, anti-migratory and vasodilatory effects. Its efficacy has been documented in several kinds of clinical trials and observational studies. This review specifically highlights the development of soluble epoxide hydrolase inhibitors (sEHIs) in the clinical setting for the management of metabolic syndrome and related disorders such as cardiovascular effects, endothelial dysfunction, arterial disease, hypertension, diabetes, obesity, heart failure, and dyslipidemia. In addition, limitations and future aspects of sEHIs have also been highlighted which will help the investigators to bring the sEHI to the clinics.

In Vitro and In Silico Studies of Soluble Epoxide Hydrolase Inhibitors from the Roots of Lycopus lucidus

Soluble epoxide hydrolase (sEH) is an enzyme that is considered a potential therapeutic target in human cardiovascular disease. Triterpenes (1–4) and phenylpropanoids (5–10) were isolated from Lycopus lucidus to obtain sEH inhibitors through various chromatographic purificationtechniques. The isolated compounds were evaluated for their inhibitory activity against sEH, and methyl rosmarinate (7), martynoside (8), dimethyl lithospermate (9) and 9″ methyl lithospermate (10) showed remarkable inhibitory activity, with the IC50 values ranging from 10.6 ± 3.2 to 35.7 ± 2.1 µM. Kinetic analysis of these compounds revealed that 7, 9 and 10 were competitive inhibitors bound to the active site, and 8 was the preferred mixed type inhibitor for allosteric sites. Additionally, molecular modeling has identified interacting catalytic residues and bindings between sEH and inhibitors. The results suggest that these compounds are potential candidates that can be used for further development in the prevention and treatment for cardiovascular risk.