Inhibition of NAADP signalling on reperfusion protects the heart by preventing lethal calcium oscillations via two-pore channel 1 and opening of the mitochondrial permeability transition pore

Davidson, Sean M., Foote, Kirsty, Kunuthur, Suma, Gosain, Raj, Tan, Noah, Tyser, Richard, Zhao, Yong Juan, Graeff, Richard, Ganesan, A., Duchen, Michael R., Patel, Sandip and Yellon, Derek M. (2016) Inhibition of NAADP signalling on reperfusion protects the heart by preventing lethal calcium oscillations via two-pore channel 1 and opening of the mitochondrial permeability transition pore. Cardiovascular Research, 108 (3). pp. 357-366. ISSN 0008-6363

[img]
Preview
PDF (Davidson et al (2015)) - Published Version
Download (756kB) | Preview

Abstract

Aims In the heart, a period of ischaemia followed by reperfusion evokes powerful cytosolic Ca2+ oscillations that can cause lethal cell injury. These signals represent attractive cardioprotective targets, but the underlying mechanisms of genesis are ill-defined. Here, we investigated the role of the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP), which is known in several cell types to induce Ca2+ oscillations that initiate from acidic stores such as lysosomes, likely via two-pore channels (TPCs, TPC1 and 2). Methods and results An NAADP antagonist called Ned-K was developed by rational design based on a previously existing scaffold. Ned-K suppressed Ca2+ oscillations and dramatically protected cardiomyocytes from cell death in vitro after ischaemia and reoxygenation, preventing opening of the mitochondrial permeability transition pore. Ned-K profoundly decreased infarct size in mice in vivo. Transgenic mice lacking the endo-lysosomal TPC1 were also protected from injury. Conclusion NAADP signalling plays a major role in reperfusion-induced cell death and represents a potent pathway for protection against reperfusion injury.

Item Type: Article
Additional Information: C The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cite
Uncontrolled Keywords: calcium,ischaemia,lysosomes,naadp,reperfusion
Faculty \ School:
Faculty of Science > School of Chemistry
Faculty of Science > School of Pharmacy
Related URLs:
Depositing User: Pure Connector
Date Deposited: 12 Jan 2016 13:00
Last Modified: 17 Mar 2020 21:24
URI: https://ueaeprints.uea.ac.uk/id/eprint/56232
DOI: 10.1093/cvr/cvv226

Actions (login required)

View Item View Item