Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Ap39, a mitochondria-targeting hydrogen sulfide (H2 s) donor, protects against myocardial reperfusion injury independently of salvage kinase signalling

Karwi, Qutuba G., Bornbaum, Julia, Boengler, Kerstin, Torregrossa, Roberta, Whiteman, Matthew, Wood, Mark E., Schulz, Rainer and Baxter, Gary F. ORCID: https://orcid.org/0000-0002-7887-6841 2017. Ap39, a mitochondria-targeting hydrogen sulfide (H2 s) donor, protects against myocardial reperfusion injury independently of salvage kinase signalling. British Journal of Pharmacology 174 (4) , pp. 287-301. 10.1111/bph.13688

[thumbnail of AP39, A MITOCHONDRIA-TARGETING HYDROGEN SULFIDE (H2S) DONOR, PROTECTS AGAINST MYOCARDIAL REPERFUSION INJURY  INDEPENDENTLY OF SALVAGE KINASE SIGNALLING .pdf]
Preview
PDF - Accepted Post-Print Version
Download (653kB) | Preview

Abstract

Background and Purpose H2S 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 H2S 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 H2S to mitochondria may be therapeutically applicable for harnessing the cardioprotective utility of H2S. This article is protected by copyright. All rights reserved.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: postconditioning; hydrogen sulfide; ischaemia-reperfusion; myocardial infarction; reperfusion; mitochondria-targeting
Publisher: Wiley
ISSN: 0007-1188
Date of First Compliant Deposit: 20 December 2016
Date of Acceptance: 5 December 2016
Last Modified: 08 Nov 2023 10:46
URI: https://orca.cardiff.ac.uk/id/eprint/96997

Citation Data

Cited 46 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics