Ravinder Kodela - Cardioprotective effect of a dual acting epoxyeicosatrienoic acid analogue towards ischaemia reperfusion injury

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      Publication Details (including relevant citation   information):

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

        Batchu S,   Lee S,   Qadhi R,   Chaudhary K,   El-Sikhry H,   Kodela R,   Falck J,   Seubert J.

      Br J Pharmacol. 2010   Oct 29. doi: 10.1111/j.1476-5381.2010.01093.x. [Epub ahead of   print]

      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   to 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 ΔΨm 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.

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