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. Epub 2015 Sep 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channels / deficiency
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium Signaling / drug effects*
  • Carbolines / pharmacology*
  • Cytoprotection
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria, Heart / drug effects*
  • Mitochondria, Heart / metabolism
  • Mitochondria, Heart / pathology
  • Mitochondrial Membrane Transport Proteins / antagonists & inhibitors*
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Permeability Transition Pore
  • Mitochondrial Swelling / drug effects
  • Myocardial Infarction / genetics
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • Myocardial Infarction / prevention & control*
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • NADP / analogs & derivatives*
  • NADP / antagonists & inhibitors
  • NADP / metabolism
  • Piperazines / pharmacology*
  • Rats, Sprague-Dawley
  • Time Factors


  • 1-(3-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid
  • Calcium Channels
  • Carbolines
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Ned-K compound
  • Piperazines
  • TPCN1 protein, mouse
  • NADP