Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication




Journal article


Cardiovasc Res

Publication Date





357 - 366


Calcium, Ischaemia, Lysosomes, NAADP, Reperfusion, Animals, Calcium Channels, Calcium Signaling, Carbolines, Cytoprotection, Disease Models, Animal, Dose-Response Relationship, Drug, Male, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Heart, Mitochondrial Membrane Transport Proteins, Mitochondrial Swelling, Myocardial Infarction, Myocardial Reperfusion Injury, Myocytes, Cardiac, NADP, Piperazines, Rats, Sprague-Dawley, Time Factors