Fasting increases susceptibility to acute myocardial ischaemia/reperfusion injury through a sirtuin-3 mediated increase in fatty acid oxidation.

Fasting increases susceptibility to acute myocardial ischaemia/reperfusion injury (IRI) but the mechanisms are unknown. Here, we investigate the role of the mitochondrial NAD+-dependent deacetylase, Sirtuin-3 (SIRT3), which has been shown to influence fatty acid oxidation and cardiac outcomes, as a potential mediator of this effect. Fasting was shown to shift metabolism from glucose towards fatty acid oxidation. This change in metabolic fuel substrate utilisation increased myocardial infarct size in wild-type (WT), but not SIRT3 heterozygous knock-out (KO) mice. Further analysis revealed SIRT3 KO mice were better adapted to starvation through an improved cardiac efficiency, thus protecting them from acute myocardial IRI. Mitochondria from SIRT3 KO mice were hyperacetylated compared to WT mice which may regulate key metabolic processes controlling glucose and fatty acid utilisation in the heart. Fasting and the associated metabolic switch to fatty acid respiration worsens outcomes in WT hearts, whilst hearts from SIRT3 KO mice are better adapted to oxidising fatty acids, thereby protecting them from acute myocardial IRI

Ap39, A Mitochondria-Targeting Hydrogen Sulfide (H2 s) Donor, Protects Against Myocardial Reperfusion Injury Independently Of Salvage Kinase Signalling.

Published onlineJournal ArticleThis is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.BACKGROUND AND PURPOSE: H2 S protects myocardium against ischaemia-reperfusion injury. This protection may involve the cytosolic reperfusion injury salvage kinase (RISK) pathway, but direct effects on mitochondrial function are possible. Here, we investigated the potential cardioprotective effect of mitochondria-specific H2 S donor, AP39, at reperfusion against ischaemia/reperfusion injury. EXPERIMENTAL APPROACH: Anaesthetised rats underwent myocardial (30 min ischaemia/120 min reperfusion) with randomisation to receive interventions prior to reperfusion: vehicle, AP39 (0.01, 0.1, 1 µmol kg(-1) ), or the control compounds AP219 or ADT-OH (1 µmol kg(-1) ). LY294002, L-NAME or ODQ were used to interrogate the involvement of RISK pathway. Myocardial samples harvested 5 minutes after reperfusion were analysed for RISK protein phosphorylation and additional experiments were conducted on isolated cardiac mitochondria to examine the direct mitochondrial effects of AP39. KEY RESULTS: AP39 exerted dose-dependent infarct size limitation. Inhibition of either PI3K/Akt, eNOS or sGC did not affect the infarct limitation of AP39. Western blot analysis confirmed that AP39 did not induce phosphorylation of Akt, eNOS, GSK-3β or ERK1/2. In isolated subsarcolemmal and interfibrillar mitochondria, AP39 significantly attenuated mitochondrial ROS generation without affecting respiratory complexes I or II. Further, AP39 inhibited mitochondrial permeability transition pore (PTP) opening and co-incubation of mitochondria with AP39 and cyclosporine A induced an additive inhibition of PTP. CONCLUSION AND IMPLICATIONS: AP39 protects against reperfusion injury independently of the cytosolic RISK pathway. Cardioprotection could be mediated by inhibiting PTP via cyclophilin D-independent mechanism. Thus, selective delivery of H2 S to mitochondria may be therapeutically applicable for harnessing the cardioprotective utility of H2 S. This article is protected by copyright. All rights reserved.QK acknowledges the generous support of the Iraqi Ministry of Higher Education and Scientific Research. RT is the recipient of The Brian Ridge Scholarship. MW and MEW would like to thank the Medical Research Council (UK) MR/M022706/1 for their generous support. Authors also thank Elvira Ungefug, Anna Reis, Sabrina Bohme and Christine Hirschhauser for their support