New insights into epoxyeicosatrienoic acid-mediated protective effects in cardiac cells

Abstract

Epoxyeicosatrienoic acids (EET) are cytochrome P450 epoxygenase metabolites of arachidonic acid. Evidence shows that they mediate protective effects in the cardiovascular system promoting cell survival. In this thesis, the major focus was to investigate if and how EETs regulate autophagy in cardiac cells during starvation. We used a dual-acting synthetic analog, UA-8 (13-(3-propylureido)tridec-8-enoic acid), possessing EET-mimetic and soluble epoxide hydrolase inhibitory properties. Our results demonstrated that UA-8 modulated an autophagic response in starved cells improving cell viability and enhancing recovery. Furthermore, UA-8 reduced both caspase-3 and total proteasome activities. Genetic as well as pharmacological inhibition of autophagy abolished the UA-8-mediated protective effects. Mechanistic studies demonstrated that sarcolemmal ATP-sensitive potassium channels and activation of AMPK are involved in the UA-8-mediated protective effects including modulation of autophagic response. Our findings provide new evidence highlighting an important role of the autophagic response in the EET-mediated survival of cardiac cells.