title: Through modulation of cardiac Ca2+handling, UCP2 affects cardiac electrophysiology and influences the susceptibility for Ca2+-mediated arrhythmias.
abstract: What is the central question of this study? Knockdown of UCP2 reduces mitochondrial Ca2+uptake. This suggests that Ucp2 knockout mice need to have additional effects on cytosolic Ca2+handling to prevent Ca2+overload. However, the specific mechanisms and their impact on cardiac electrophysiology remain speculative. What is the main finding and its importance? In Ucp2 knockout mice, decreased mitochondrial Ca2+uptake is compensated for by functional inhibition of L-type Ca2+channels and resultant shortening of action potential duration. UCP2-dependent modulations have a major impact on cardiac electrophysiology, resulting in alterations of ECG characteristics and a higher susceptibility to Ca2+-mediated ventricular arrhythmias. Uncoupling protein 2 (mitochondrial, proton carrier) (UCP2) belongs to a superfamily of mitochondrial ion transporters. Owing to its beneficial influence on production of reactive oxygen species, it is suggested to reduce cardiac ischaemia-reperfusion injury. Recent studies have uncovered its ability to regulate mitochondrial Ca2+uptake and therefore to influence cardiac cytosolic Ca2+handling, indicating compensatory pathways to avoid toxic Ca2+overload in Ucp2 knockout (Ucp2-/-) mice. However, the specific mechanisms and their impact on cardiac electrophysiology remain speculative. Molecular analyses, whole-cell patch clamp in cardiomyocytes and ECG studies were performed in Ucp2-/-and wild-type (WT) control mice. Furthermore, to explore the impact on cardiac arrhythmogenicity, ECG monitoring was performed in basal conditions and during Ca2+-mediated stress using Bay K 8644. Although cardiac ryanodine receptor 2, NCX1, L-type Ca2+channel (LTCC) and SERCA2a expression were not altered, Ucp2-/-mice revealed major variations in cardiac electrophysiology. The LTCC current and APD90were decreased in Ucp2-/-mice, indicating compensatory mechanisms. Furthermore, in Ucp2-/-mice, an increased slope factor of action potential upstrokes and more hyperpolarized resting membrane potential were measured, suggesting variations in cardiac excitability. In agreement with alterations of cellular physiology in Ucp2-/-mice, reductions in PR and QRS as well as shortening of the QTc interval were noted in ECG recordings. Importantly, an increased incidence of cellular after-depolarizations and more pronounced susceptibility to Ca2+-mediated arrhythmias were observed. Furthermore, although expression of UCP3 was not different, levels of PRMT1 were significantly higher in Ucp2-/-mice. Our observations indicate compensatory mechanisms by which Ucp2-/-mice prevent toxic cytosolic Ca2+overload. UCP2-dependent modulations have a major impact on cardiac electrophysiology and influence susceptibility to Ca2+-mediated ventricular arrhythmias.
authors.affiliation: Department of Internal Medicine II, Paracelsus Medical University/SALK, Salzburg, Austria.|Division of Electrophysiology, Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Larbig
authors.affiliation: Department of Internal Medicine II, Paracelsus Medical University/SALK, Salzburg, Austria.
authors.forename: Sara
authors.initials: S
authors.lastname: Reda
authors.affiliation: Department of Internal Medicine II, Paracelsus Medical University/SALK, Salzburg, Austria.
authors.forename: Vera
authors.initials: V
authors.lastname: Paar
authors.affiliation: Research Program for Ophthalmology and Glaucoma Research, University Clinic of Ophthalmology and Optometry, Paracelsus Medical University/SALK, Salzburg, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Trost
authors.affiliation: Department of Internal Medicine II, Paracelsus Medical University/SALK, Salzburg, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Leitner
authors.affiliation: Department of Internal Medicine II, Paracelsus Medical University/SALK, Salzburg, Austria.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Weichselbaumer
authors.affiliation: Research Program for Ophthalmology and Glaucoma Research, University Clinic of Ophthalmology and Optometry, Paracelsus Medical University/SALK, Salzburg, Austria.
authors.forename: Karolina A
authors.initials: KA
authors.lastname: Motloch
authors.affiliation: Department of Internal Medicine II, Paracelsus Medical University/SALK, Salzburg, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wernly
authors.affiliation: Department of Internal Medicine II, Paracelsus Medical University/SALK, Salzburg, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Arrer
authors.affiliation: Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Strauss
authors.affiliation: Department of Internal Medicine II, Paracelsus Medical University/SALK, Salzburg, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Lichtenauer
authors.affiliation: Research Program for Ophthalmology and Glaucoma Research, University Clinic of Ophthalmology and Optometry, Paracelsus Medical University/SALK, Salzburg, Austria.
authors.forename: Herbert A
authors.initials: HA
authors.lastname: Reitsamer
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Eckardt
authors.affiliation: Institute for Genetics of Heart Diseases (IFGH), Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany.
authors.forename: Guiscard
authors.initials: G
authors.lastname: Seebohm
authors.affiliation: Department of Internal Medicine II, Paracelsus Medical University/SALK, Salzburg, Austria.
authors.forename: Uta C
authors.initials: UC
authors.lastname: Hoppe
authors.affiliation: Department of Internal Medicine II, Paracelsus Medical University/SALK, Salzburg, Austria.
authors.forename: Lukas J
authors.identifier: 0000-0002-0207-6469
authors.initials: LJ
authors.lastname: Motloch
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004594:Electrophysiology / Q000379:methods; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008929:Mitochondria, Heart / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D000071246:Uncoupling Protein 2 / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; C110374:sodium-calcium exchanger 1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: Heart; L-type calcium current; UCP2; arrhythmia; calcium; mitochondria