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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

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

Cardiovasc Res. 2015 Dec 1;108(3):357-66.

PMID: 26395965

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4244351	Ned-K			Price

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