Tools
Tools
Davidson, Sean M., Foote, Kirsty, Kunuthur, Suma, Gosain, Raj, Tan, Noah, Tyser, Richard, Zhao, Yong Juan, Graeff, Richard, Ganesan, A. 
ORCID: https://orcid.org/0000-0003-4862-7999, 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
Preview |
PDF (Davidson et al (2015))
- Published Version
Available under License Creative Commons Attribution. 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 (former - to 2024) Faculty of Science > School of Pharmacy (former - to 2024) |
| UEA Research Groups: | Faculty of Science > Research Groups > Medicinal Chemistry (former - to 2017) Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021) |
| Related URLs: | |
| Depositing User: | Pure Connector |
| Date Deposited: | 12 Jan 2016 13:00 |
| Last Modified: | 21 Oct 2024 23:42 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/56232 |
| DOI: | 10.1093/cvr/cvv226 |
Downloads
Downloads per month over past year
Actions (login required)
 |
View Item |