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

Sean M. Davidson, Kirsty Foote, Suma Kunuthur, Raj Gosain, Noah Tan, Richard Tyser, Yong Juan Zhao, Richard Graeff, A. Ganesan, Michael R. Duchen, Sandip Patel, Derek M. Yellon

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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.

Original languageEnglish
Pages (from-to)357-366
Number of pages10
JournalCardiovascular Research
Volume108
Issue number3
Early online date22 Sep 2015
DOIs
Publication statusPublished - 1 Dec 2016

Keywords

  • Calcium
  • Ischaemia
  • Lysosomes
  • NAADP
  • Reperfusion

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