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.

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.

• Authors: 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
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 108 Issue 3 Pg. 357-66 (Dec 01 2015) ISSN: 1755-3245 [Electronic] England
• PMID: 26395965 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

Chemical References

• 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
• NAADP

Topics

• Animals
• Calcium Channels (deficiency, genetics, 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, metabolism, pathology)
• Mitochondrial Membrane Transport Proteins (antagonists & inhibitors, metabolism)
• Mitochondrial Permeability Transition Pore
• Mitochondrial Swelling (drug effects)
• Myocardial Infarction (genetics, metabolism, pathology, prevention & control)
• Myocardial Reperfusion Injury (genetics, metabolism, pathology, prevention & control)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• NADP (analogs & derivatives, antagonists & inhibitors, metabolism)
• Piperazines (pharmacology)
• Rats, Sprague-Dawley
• Time Factors