2. Academic Validation
  3. AP39, a mitochondria-targeting hydrogen sulfide (H2 S) donor, protects against myocardial reperfusion injury independently of salvage kinase signalling

AP39, a mitochondria-targeting hydrogen sulfide (H2 S) donor, protects against myocardial reperfusion injury independently of salvage kinase signalling

  • Br J Pharmacol. 2017 Feb;174(4):287-301. doi: 10.1111/bph.13688.
Qutuba G Karwi 1 2,  Julia Bornbaum 3,  Kerstin Boengler 3,  Roberta Torregrossa 4 5,  Matthew Whiteman 4,  Mark E Wood 5,  Rainer Schulz 3,  Gary F Baxter 1
Affiliations

Affiliations

  • 1 School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK.
  • 2 College of Medicine, University of Diyala, Diyala, Iraq.
  • 3 Institute of Physiology, Justus-Liebig-University, Giessen, Germany.
  • 4 Medical School, University of Exeter, Exeter, UK.
  • 5 School of Biosciences, University of Exeter, Exeter, UK.
PMID: 27930802 DOI: 10.1111/bph.13688
Abstract

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 a mitochondria-specific H2 S donor, AP39, at reperfusion against ischaemia/reperfusion injury.

Experimental approach: Anaesthetized rats underwent myocardial ischaemia (30 min)/reperfusion (120 min) with randomization to receive interventions before reperfusion: vehicle, AP39 (0.01, 0.1, 1 μmol·kg-1 ), or control compounds AP219 and ADT-OH (1 μmol·kg-1 ). LY294002, L-NAME or ODQ were used to investigate the involvement of the RISK pathway. Myocardial samples harvested 5 min after reperfusion were analysed for RISK protein phosphorylation and isolated cardiac mitochondria were used to examine the direct mitochondrial effects of AP39.

Key results: AP39, dose-dependently, reduced infarct size. Inhibition of either PI3K/Akt, eNOS or sGC did not affect this effect 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. Furthermore, AP39 inhibited mitochondrial permeability transition pore (PTP) opening and co-incubation of mitochondria with AP39 and cyclosporine A induced an additive inhibitory effect on the PTP.

Conclusion and implications: AP39 protects against reperfusion injury independently of the cytosolic RISK pathway. This cardioprotective effect could be mediated by inhibiting PTP via a cyclophilin D-independent mechanism. Thus, selective delivery of H2 S to mitochondria may be therapeutically applicable for employing the cardioprotective utility of H2 S.

Figures
Products