Dataset Information

Cardioprotective effect of a dual acting epoxyeicosatrienoic acid analogue towards ischaemia reperfusion injury.

ABSTRACT:

Background and purpose

Epoxyeicosatrienoic acids (EETs) are cytochrome P450 epoxygenase metabolites of arachidonic acid that are metabolized into dihydroxyepoxyeicosatrienoic acids (DHET) by soluble epoxide hydrolase (sEH). The current investigations were performed to examine the cardioprotective effects of UA-8 (13-(3-propylureido)tridec-8-enoic acid), a synthetic compound that possesses both EET-mimetic and sEH inhibitory properties, against ischaemia-reperfusion injury.

Experimental approach

Hearts from C57BL/6 mice were perfused in Langendorff mode and subjected to ischaemia reperfusion. Mechanistic studies involved co-perfusing hearts with either 14,15-EEZE (a putative EET receptor antagonist), wortmannin or PI-103 (class-I PI3K inhibitor). H9c2 cells were utilized to investigate the protective effects against mitochondrial injury following anoxia reoxygenation.

Key results

Perfusion of UA-8 significantly improved postischaemic left ventricular developed pressure (LVDP) and reduced infarction following ischaemia reperfusion compared with control and 11,12-EET. UA-7 (13-(2-(butylamino)-2-oxoacetamido)tridec-8(Z)-enoic acid), a compound lacking sEH inhibitory properties, also improved postischaemic LVDP, while co-perfusion with 14,15-EEZE, wortmannin or PI-103 attenuated the improved recovery. UA-8 prevented anoxia-reoxygenation induced loss of mitochondrial membrane potential and cell death in H9c2 cells, which was blocked by co-treatment of PI-103.

Conclusions and implications

UA-8 provides significant cardioprotection against ischaemia reperfusion injury. The effects are attributed to EETs mimetic properties, which limits mitochondrial dysfunction via class-I PI3K signalling.

SUBMITTER: Batchu SN

PROVIDER: S-EPMC3042200 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cardioprotective effect of a dual acting epoxyeicosatrienoic acid analogue towards ischaemia reperfusion injury.

Batchu S N SN Lee S B SB Qadhi R S RS Chaudhary K R KR El-Sikhry H H Kodela R R Falck J R JR Seubert J M JM

British journal of pharmacology 20110201 4

<h4>Background and purpose</h4>Epoxyeicosatrienoic acids (EETs) are cytochrome P450 epoxygenase metabolites of arachidonic acid that are metabolized into dihydroxyepoxyeicosatrienoic acids (DHET) by soluble epoxide hydrolase (sEH). The current investigations were performed to examine the cardioprotective effects of UA-8 (13-(3-propylureido)tridec-8-enoic acid), a synthetic compound that possesses both EET-mimetic and sEH inhibitory properties, against ischaemia-reperfusion injury.<h4>Experimenta ...[more]

PMID: 21039415

Similar Datasets

Project description:BackgroundAlthough early reperfusion is the most desirable intervention after ischemic myocardial insult, it may add to damage through oxidative stress.ObjectivesThis study investigated the cardioprotective effects of a single intravenous dose of heat shock protein-72 (HSP72) coupled to a single-chain variable fragment (Fv) of monoclonal antibody 3E10 (3E10Fv) in a rabbit ischemia-reperfusion model. The Fv facilitates rapid transport of HSP72 into cells, even with intact membranes.MethodsA left coronary artery occlusion (40 min) reperfusion (3 h) model was used in 31 rabbits. Of these, 12 rabbits received the fusion protein (Fv-HSP72) intravenously. The remaining 19 control rabbits received a molar equivalent of 3E10Fv alone (n = 6), HSP72 alone (n = 6), or phosphate-buffered saline (n = 7). Serial echocardiographic examinations were performed to assess left ventricular function before and after reperfusion. Micro-single-photon emission computed tomography imaging of 99mTc-labeled annexin-V was performed with micro-computed tomography scanning to characterize apoptotic damage in vivo, followed by gamma counting of the excised myocardial specimens to quantify cell death. Histopathological characterization of the myocardial tissue and sequential cardiac troponin I measurements were also undertaken.ResultsMyocardial annexin-V uptake was 43% lower in the area at risk (p = 0.0003) in Fv-HSP72-treated rabbits compared with control animals receiving HSP72 or 3E10Fv alone. During reperfusion, troponin I release was 42% lower and the echocardiographic left ventricular ejection fraction 27% higher in the Fv-HSP72-treated group compared with control animals. Histopathological analyses confirmed penetration of 3E10Fv-containing molecules into cardiomyocytes in vivo, and treatment with Fv-HSP72 showed fewer apoptotic nuclei compared with control rabbits.ConclusionsSingle-dose administration of Fv-HSP72 fusion protein at the time of reperfusion reduced myocardial apoptosis by almost one-half and improved left ventricular functional recovery after myocardial ischemia-reperfusion injury in rabbits. It might have potential to serve as an adjunct to early reperfusion in the management of myocardial infarction.

Dataset Information

Cardioprotective effect of a dual acting epoxyeicosatrienoic acid analogue towards ischaemia reperfusion injury.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Cardioprotective effect of a dual acting epoxyeicosatrienoic acid analogue towards ischaemia reperfusion injury.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets