2. Academic Validation
  3. 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

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

  • Cardiovasc Res. 2015 Dec 1;108(3):357-66. doi: 10.1093/cvr/cvv226.
Sean M Davidson 1,  Kirsty Foote 2,  Suma Kunuthur 2,  Raj Gosain 3,  Noah Tan 2,  Richard Tyser 2,  Yong Juan Zhao 4,  Richard Graeff 4,  A Ganesan 5,  Michael R Duchen 6,  Sandip Patel 6,  Derek M Yellon 2
Affiliations

Affiliations

  • 1 The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, WC1E 6HX London, UK s.davidson@ucl.ac.uk.
  • 2 The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, WC1E 6HX London, UK.
  • 3 School of Chemistry, University of Southampton, Highfield, Southampton, UK.
  • 4 Department of Physiology, Li Ka Shing School of Medicine, The University of Hong Kong, Hong Kong, China.
  • 5 School of Pharmacy, University of East Anglia, Norwich, UK.
  • 6 Department of Cell and Developmental Biology, University College London, London, UK.
PMID: 26395965 DOI: 10.1093/cvr/cvv226
Abstract

Aims: In the heart, a period of ischaemia followed by reperfusion evokes powerful cytosolic CA(2+) 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 CA(2+) 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 CA(2+) 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.

Keywords

Calcium; Ischaemia; Lysosomes; NAADP; Reperfusion.

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