TY - JOUR
T1 - Suppression of Arrhythmia by Enhancing Mitochondrial Ca2+ Uptake in Catecholaminergic Ventricular Tachycardia Models
AU - Schweitzer, Maria K.
AU - Wilting, Fabiola
AU - Sedej, Simon
AU - Dreizehnter, Lisa
AU - Dupper, Nathan J.
AU - Tian, Qinghai
AU - Moretti, Alessandra
AU - My, Ilaria
AU - Kwon, Ohyun
AU - Priori, Silvia G.
AU - Laugwitz, Karl Ludwig
AU - Storch, Ursula
AU - Lipp, Peter
AU - Breit, Andreas
AU - Mederos y Schnitzler, Michael
AU - Gudermann, Thomas
AU - Schredelseker, Johann
N1 - Publisher Copyright:
© 2017 The Authors
PY - 2017/12
Y1 - 2017/12
N2 - Cardiovascular disease-related deaths frequently arise from arrhythmias, but treatment options are limited due to perilous side effects of commonly used antiarrhythmic drugs. Cardiac rhythmicity strongly depends on cardiomyocyte Ca2+ handling and prevalent cardiac diseases are causally associated with perturbations in intracellular Ca2+ handling. Therefore, intracellular Ca2+ transporters are lead candidate structures for novel and safer antiarrhythmic therapies. Mitochondria and mitochondrial Ca2+ transport proteins are important regulators of cardiac Ca2+ handling. Here, the authors evaluated the potential of pharmacological activation of mitochondrial Ca2+ uptake for the treatment of cardiac arrhythmia. To this aim, the authors tested substances that enhance mitochondrial Ca2+ uptake for their ability to suppress arrhythmia in a murine model for ryanodine receptor 2 (RyR2)-mediated catecholaminergic polymorphic ventricular tachycardia (CPVT) in vitro and in vivo and in induced pluripotent stem cell-derived cardiomyocytes from a CPVT patient. In freshly isolated cardiomyocytes of RyR2R4496C/WT mice efsevin, a synthetic agonist of the voltage-dependent anion channel 2 (VDAC2) in the outer mitochondrial membrane, prevented the formation of diastolic Ca2+ waves and spontaneous action potentials. The antiarrhythmic effect of efsevin was abolished by blockade of the mitochondrial Ca2+ uniporter (MCU), but could be reproduced using the natural MCU activator kaempferol. Both mitochondrial Ca2+ uptake enhancers (MiCUps), efsevin and kaempferol, significantly reduced episodes of stress-induced ventricular tachycardia in RyR2R4496C/WT mice in vivo and abolished diastolic, arrhythmogenic Ca2+ events in human iPSC-derived cardiomyocytes. These results highlight an immediate potential of enhanced mitochondrial Ca2+ uptake to suppress arrhythmogenic events in experimental models of CPVT and establish MiCUps as promising pharmacological tools for the treatment and prevention of Ca2+-triggered arrhythmias such as CPVT.
AB - Cardiovascular disease-related deaths frequently arise from arrhythmias, but treatment options are limited due to perilous side effects of commonly used antiarrhythmic drugs. Cardiac rhythmicity strongly depends on cardiomyocyte Ca2+ handling and prevalent cardiac diseases are causally associated with perturbations in intracellular Ca2+ handling. Therefore, intracellular Ca2+ transporters are lead candidate structures for novel and safer antiarrhythmic therapies. Mitochondria and mitochondrial Ca2+ transport proteins are important regulators of cardiac Ca2+ handling. Here, the authors evaluated the potential of pharmacological activation of mitochondrial Ca2+ uptake for the treatment of cardiac arrhythmia. To this aim, the authors tested substances that enhance mitochondrial Ca2+ uptake for their ability to suppress arrhythmia in a murine model for ryanodine receptor 2 (RyR2)-mediated catecholaminergic polymorphic ventricular tachycardia (CPVT) in vitro and in vivo and in induced pluripotent stem cell-derived cardiomyocytes from a CPVT patient. In freshly isolated cardiomyocytes of RyR2R4496C/WT mice efsevin, a synthetic agonist of the voltage-dependent anion channel 2 (VDAC2) in the outer mitochondrial membrane, prevented the formation of diastolic Ca2+ waves and spontaneous action potentials. The antiarrhythmic effect of efsevin was abolished by blockade of the mitochondrial Ca2+ uniporter (MCU), but could be reproduced using the natural MCU activator kaempferol. Both mitochondrial Ca2+ uptake enhancers (MiCUps), efsevin and kaempferol, significantly reduced episodes of stress-induced ventricular tachycardia in RyR2R4496C/WT mice in vivo and abolished diastolic, arrhythmogenic Ca2+ events in human iPSC-derived cardiomyocytes. These results highlight an immediate potential of enhanced mitochondrial Ca2+ uptake to suppress arrhythmogenic events in experimental models of CPVT and establish MiCUps as promising pharmacological tools for the treatment and prevention of Ca2+-triggered arrhythmias such as CPVT.
KW - CPVT
KW - MCU
KW - MiCUp
KW - RyR2
KW - VDAC2
KW - mitochondria
UR - http://www.scopus.com/inward/record.url?scp=85040771865&partnerID=8YFLogxK
U2 - 10.1016/j.jacbts.2017.06.008
DO - 10.1016/j.jacbts.2017.06.008
M3 - Article
AN - SCOPUS:85040771865
SN - 2452-302X
VL - 2
SP - 737
EP - 747
JO - JACC: Basic to Translational Science
JF - JACC: Basic to Translational Science
IS - 6
ER -