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 Ca uptake. This suggests that Ucp2 knockout mice need to have additional effects on cytosolic Ca handling to prevent Ca 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 Ca uptake is compensated for by functional inhibition of L-type Ca 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 Ca -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 Ca uptake and therefore to influence cardiac cytosolic Ca handling, indicating compensatory pathways to avoid toxic Ca 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 Ca -mediated stress using Bay K 8644. Although cardiac ryanodine receptor 2, NCX1, L-type Ca channel (LTCC) and SERCA2a expression were not altered, Ucp2 mice revealed major variations in cardiac electrophysiology. The LTCC current and APD 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 Ca -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 Ca overload. UCP2-dependent modulations have a major impact on cardiac electrophysiology and influence susceptibility to Ca -mediated ventricular arrhythmias.

Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox SignalingReviewing Editors:Jerzy Beltowski, Joseph Burgoyne, Gabor Csanyi, Sergey Dikalov, Frank Krause, Anibal Vercesi, and Jeremy Ward

“…UCP2 has also been shown to participate in cardiac Ca 2+ handling, influencing susceptibility for Ca 2+ -mediated arrhythmias ( 240 ). In addition, cytoprotection by UCP2 attenuation of apoptosis in tubular epithelial cells has been reported in case of renal ischemia/reperfusion injury ( 452 ).…”

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“…The prevalence of chronic kidney disease was also higher in the group with prolonged QTc, an observation that is also related to electrolyte disturbances and secondary hyperparathyroidism 31. These data might lead to the assumption that the intracellular electrolyte disturbances found in COPD patients might contribute to prolonged QTc 32. Previous studies has demonstrated a change in PTH in COPD patients.…”

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“…Disturbances in functioning of the mtCU regulators are also associated with the development of arrhythmias. For instance, Ucp2−/− mice have more pronounced susceptibility to the Ca 2+ overload-induced arrhythmias and increased PRMT1 protein levels, which may be responsible for the decreased mitochondrial Ca 2+ -uptake in the Ucp2−/− hearts [111]. It is important to note that the UCP polymorphisms in humans are known to be associated with the heart rate variability [112].…”