Effect of Soluble Epoxide Hydrolase on the Modulation of Coronary Reactive Hyperemia: Role of Oxylipins and PPARγ

Coronary reactive hyperemia (CRH) is a physiological response to ischemic insult that prevents the potential harm associated with an interruption of blood supply. The relationship between the pharmacologic inhibition of soluble epoxide hydrolase (sEH) and CRH response to a brief ischemia is not known. sEH is involved in the main catabolic pathway of epoxyeicosatrienoic acids (EETs), which are converted into dihydroxyeicosatrienoic acids (DHETs). EETs protect against ischemia/reperfusion injury and have numerous beneficial physiological effects. We hypothesized that inhibition of sEH by t-AUCB enhances CRH in isolated mouse hearts through changing the oxylipin profiles, including an increase in EETs/DHETs ratio. Compared to controls, t-AUCB–treated mice had increased CRH, including repayment volume (RV), repayment duration, and repayment/debt ratio (p \u3c 0.05). Treatment with t-AUCB significantly changed oxylipin profiles, including an increase in EET/DHET ratio, increase in EpOME/DiHOME ratio, increase in the levels of HODEs, decrease in the levels of mid-chain HETEs, and decrease in prostanoids (p \u3c 0.05). Treatment with MS-PPOH (CYP epoxygenase inhibitor) reduced CRH, including RV (p \u3c 0.05). Involvement of PPARγ in the modulation of CRH was demonstrated using a PPARγ-antagonist (T0070907) and a PPARγ-agonist (rosiglitazone). T0070907 reduced CRH (p \u3c 0.05), whereas rosiglitazone enhanced CRH (p \u3c 0.05) in isolated mouse hearts compared to the non-treated. These data demonstrate that sEH inhibition enhances, whereas CYP epoxygenases-inhibition attenuates CRH, PPARγ mediate CRH downstream of the CYP epoxygenases-EET pathway, and the changes in oxylipin profiles associated with sEH-inhibition collectively contributed to the enhanced CRH

Vascular Endothelial Over-Expression of Human Soluble Epoxide Hydrolase (Tie2-sEH Tr) Attenuates Coronary Reactive Hyperemia in Mice: Role of Oxylipins and ω-Hydroxylases

Cytochromes P450 metabolize arachidonic acid (AA) into two vasoactive oxylipins with opposing biologic effects: epoxyeicosatrienoic acids (EETs) and omega-(ω)-terminal hydroxyeicosatetraenoic acids (HETEs). EETs have numerous beneficial physiological effects, including vasodilation and protection against ischemia/reperfusion injury, whereas ω-terminal HETEs induce vasoconstriction and vascular dysfunction. We evaluated the effect of these oxylipins on post-ischemic vasodilation known as coronary reactive hyperemia (CRH). CRH prevents the potential harm associated with transient ischemia. The beneficial effects of EETs are reduced after their hydrolysis to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). ω-terminal HETEs are formed by ω-hydroxylase family members. The relationship among endothelial over-expression of sEH (Tie2-sEH Tr), the changes in oxylipins it may produce, the pharmacologic inhibition of ω-hydroxylases, activation of PPARγ, and CRH response to a brief ischemia is not known. We hypothesized that CRH is attenuated in isolated mouse hearts with endothelial sEH over-expression through modulation of oxylipin profiles, whereas both inhibition of ω-hydroxylases and activation of PPARγ enhance CRH. Compared to WT mice, Tie2-sEH Tr mice had decreased CRH, including repayment volume, repayment duration, and repayment/debt ratio (P \u3c 0.05), whereas inhibition of ω-hydroxylases increased these same CRH parameters in Tie2-sEH Tr mice. Inhibition of sEH with t-AUCB reversed the decreased CRH in Tie2-sEH Tr mice. Endothelial over-expression of sEH significantly changed oxylipin profiles, including decreases in DHETs, mid-chain HETEs, and prostaglandins (P \u3c 0.05). Treatment with rosiglitazone, PPARγ-agonist, enhanced CRH (P \u3c 0.05) in both Tie2-sEH Tr and wild type (WT) mice. These data demonstrate that endothelial over-expression of sEH (through changing the oxylipin profiles) attenuates CRH, whereas inhibition of ω-hydroxylases and activation of PPARγ enhance it

ОСВОБОЖДЕНИЕ ОБРАЩЕНИЯ С ТЕХНОГЕННЫМИ ИСТОЧНИКАМИ ИОНИЗИРУЮЩЕГО ИЗЛУЧЕНИЯ ОТ СПЕЦИАЛЬНОЙ РЕГЛАМЕНТАЦИИ

An article considers normative providing of the procedure of the exception of management of different types of artificial ionizing irradiation sources from the special regulation. The discrepancy is pointed out in the existing set of normative documents in mentioned area and the complexity of the university in the practical applying of these documents. It is pointed out that exception of management of ionizing irradiation sources from control and registration means the full exception from the special regulation and that the document that proves such exception is sanitary-epidemiological resolution. The attempt is made to suggest reasonable and uniform approach to the procedure of the exception of management of all types of artificial ionizing irradiation from registration and control and to the necessity of license registration with the account of demands of all valid normative documents.В статье рассмотрено нормативное обеспечение процедуры освобождения обращения с различными видами техногенных источников ионизирующего излучения от специальной регламентации. Отмечена противоречивость имеющегося набора нормативных документов в этой области и сложность их однозначного практического применения. Отмечено, что освобождение обращения с источниками ионизирующего излучения от учета и контроля означает полное освобождение от специальной регламентации и что документом, подтверждающим такое освобождение, является санитарно-эпидемиологическое заключение. Сделана попытка предложить разумный и единообразный подход к процедуре освобождения обращения со всеми видами техногенных источников ионизирующего излучения от учета, контроля и необходимости оформления лицензии с учетом требований действующих нормативных документов

Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study

Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD). The relationship between circulating EET levels and CAD extent in humans, however, remains unknown. A panel of free (unesterified) plasma eicosanoid metabolites was quantified in 162 patients referred for coronary angiography, and associations with extent of CAD [no apparent CAD (N = 39), nonobstructive CAD (N = 51), and obstructive CAD (N = 72)] were evaluated. A significant relationship between free EET levels and CAD extent was observed (P = 0.003) such that the presence of obstructive CAD was associated with lower circulating EET levels. This relationship was confirmed in multiple regression analysis where CAD extent was inversely and significantly associated with EET levels (P = 0.013), and with a biomarker of EET biosynthesis (P < 0.001), independent of clinical and demographic factors. Furthermore, quantitative enrichment analysis revealed that these associations were the most pronounced compared with other eicosanoid metabolism pathways. Collectively, these findings suggest that the presence of obstructive CAD is associated with lower EET metabolite levels secondary to suppressed EET biosynthesis. Novel strategies that promote the effects of EETs may have therapeutic promise for patients with obstructive CAD

ВЫБРОС ПРИРОДНЫХ РАДИОНУКЛИДОВ В ОКРУЖАЮЩУЮ СРЕДУ В РЕЗУЛЬТАТЕ ДЕЯТЕЛЬНОСТИ ПРЕДПРИЯТИЙ НЕЯДЕРНЫХ ОТРАСЛЕЙ

In the present overview we analyze the literary data concerning discharges of natural radionuclides into the environment due to functioning of the enterprises of non-nuclear industries. We consider their quantitative characteristics of discharges, the peculiarities of the formation of radionuclide composition of discharges from various industrial branches, the information about the population exposure doses due to these discharges, as well as the possibilities of standardization of the industrial discharges of natural radionuclides. В настоящем обзоре анализируются литературные данные о выбросе природных радионуклидов в окружающую среду за счет деятельности предприятий неядерных отраслей. Рассматриваются количественные характеристики выбросов, особенности формирования радионуклидного состава выбросов предприятиями разных отраслей и сведения о дозах облучения населения за счет выбросов, а также возможности нормирования величины выброса природных радионуклидов за счет деятельности предприятий