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
  • 1. The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, WC1E 6HX London, UK [email protected].
  • 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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