Cardioprotective effect of 19,20-epoxydocosapentaenoic acid (19,20-EDP) in ischaemic injury involves direct activation of mitochondrial sirtuin 3

Abstract

Aims: Although current clinical therapies following myocardial infarction (MI) have improved patient outcomes, morbidity, and mortality rates, secondary to ischaemic and ischaemia reperfusion (IR) injury remains high. Maintaining mitochondrial quality is essential to limit myocardial damage following cardiac ischaemia and IR injury. The mitochondrial deacetylase sirtuin 3 (SIRT3) plays a pivotal role in regulating mitochondrial function and cardiac energy metabolism. In the current study, we hypothesize that 19,20-epoxydocosapentaenoic acid (19,20-EDP) attenuates cardiac IR injury via stimulating mitochondrial SIRT3.

Methods and results: Ex vivo models of isolated heart perfusions were performed in C57BL/6 mice to assess the effect of 19,20-EDP on cardiac function and energy metabolism following IR injury. In vivo permanent occlusion of the left anterior descending coronary artery was performed to induce MI; mice were administered 19,20-EDP with or without the SIRT3 selective inhibitor 3-TYP. Mitochondrial SIRT3 targets and respiration were assessed in human left ventricular tissues obtained from individuals with ischaemic heart disease (IHD) and compared to non-failing controls (NFCs). Binding affinity of 19,20-EDP to human SIRT3 was assessed using molecular modelling and fluorescence thermal shift assay. Results demonstrated that hearts treated with 19,20-EDP had improved post-ischaemic cardiac function, better glucose oxidation rates, and enhanced cardiac efficiency. The cardioprotective effects were associated with enhanced mitochondrial SIRT3 activity. Interestingly, treatment with 19,20-EDP markedly improved mitochondrial respiration and SIRT3 activity in human left ventricle (LV) fibres with IHD compared to NFC. Moreover, 19,20-EDP was found to bind to the human SIRT3 protein enhancing the NAD+-complex stabilization leading to improved SIRT3 activity. Importantly, the beneficial effects of 19,20-EDP were abolished by SIRT3 inhibition or using the S149A mutant SIRT3.

Conclusion: These data demonstrate that 19,20-EDP-mediated cardioprotective mechanisms against ischaemia and IR injury involve mitochondrial SIRT3, resulting in improved cardiac efficiency.

Keywords: 19,20-Epoxydocosapentaenoic acid; Ischaemic human hearts; Ischaemic injury; Mitochondria; Sirtuin 3.