Through modulation of cardiac Ca2+ handling, UCP2 affects cardiac electrophysiology and influences the susceptibility for Ca2+ -mediated arrhythmias.

ABSTRACT

NEW FINDINGS: 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 APD90 were 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.