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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

DOI

10.1093/cvr/cvv226

Type

Journal article

Journal

Cardiovasc Res

Publication Date

01/12/2015

Volume

108

Pages

357 - 366

Keywords

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