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. (22nd September 2015)

• Record Type: Journal Article
• Authors: Davidson, Sean M.; Foote, Kirsty; Kunuthur, Suma; Gosain, Raj; Tan, Noah; Tyser, Richard; Zhao, Yong Juan; Graeff, Richard; Ganesan, A.; Duchen, Michael R.; Patel, Sandip; Yellon, Derek M.
• Is Part Of: Cardiovascular research. Volume 108:Number 3(2015)
• Page Start: 357
• Page End: 366
• Publication Date: 2015-09-22
• Subjects: NAADP -- Ischaemia -- Reperfusion -- Calcium -- Lysosomes; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvv226
• Languages: English
• ISSNs: 0008-6363

Abstract

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.