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.
Keywords:
Calcium; Ischaemia; Lysosomes; NAADP; Reperfusion.
© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Calcium Channels / deficiency
-
Calcium Channels / genetics
-
Calcium Channels / 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*
-
Mitochondria, Heart / metabolism
-
Mitochondria, Heart / pathology
-
Mitochondrial Membrane Transport Proteins / antagonists & inhibitors*
-
Mitochondrial Membrane Transport Proteins / metabolism
-
Mitochondrial Permeability Transition Pore
-
Mitochondrial Swelling / drug effects
-
Myocardial Infarction / genetics
-
Myocardial Infarction / metabolism
-
Myocardial Infarction / pathology
-
Myocardial Infarction / prevention & control*
-
Myocardial Reperfusion Injury / genetics
-
Myocardial Reperfusion Injury / metabolism
-
Myocardial Reperfusion Injury / pathology
-
Myocardial Reperfusion Injury / prevention & control*
-
Myocytes, Cardiac / drug effects*
-
Myocytes, Cardiac / metabolism
-
Myocytes, Cardiac / pathology
-
NADP / analogs & derivatives*
-
NADP / antagonists & inhibitors
-
NADP / metabolism
-
Piperazines / pharmacology*
-
Rats, Sprague-Dawley
-
Time Factors
Substances
-
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