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DOI: 10.1055/s-0039-1678819
Altered Electrophysiological Remodeling Induced by Mechanical Unloading in Phospholamban Deficient Mice
Publication History
Publication Date:
28 January 2019 (online)
Background: Cardiac mechanical unloading with assist devices leads to a reverse remodeling of the unloaded heart with alterations in myocardial structure and function. Previous work has shown an impaired calcium handling with electrophysiological alterations of the unloaded heart, but the precise mechanisms are unknown. A major consequence is the activation of phospholamban (PLN) by increased dephosphorylation, leading to a shift of Ca2+ cycling from the sarcoplasmic reticulum to the plasma membrane. The aim of the study was to assess the role of PLN in electrophysiological remodeling in unloaded hearts.
Methods: Cardiac mechanical unloading was induced by heterotopic heart transplantation in littermate PLN deficient (PLN−/−) and wild-type (WT) mice, with native in situ (orthotopic) hearts serving as controls. After (2) 14 days of unloading quantitative real-time PCR, western blotting and multielectrode arrays were used to assess molecular and functional remodeling in the unloaded and orthotopic hearts.
Results: In unloaded PLN−/− hearts, a reduced expression of the voltage-gated L-type calcium channel (Cav1.2: -55%) and of the molecular components underlying the transient outward K+ current Ito (Kv4.2: -75%; Kv4.3: -46%; KChIP2: -80%) were observed. Protein levels of SERCA2a were preserved in unloaded PLN−/− hearts. Field potential (FP) duration was prolonged by 28% (from 96 ± 3 ms, n = 30 to 123 ± 3 ms, n = 18; p < 0.001) in WT mice. In unloaded PLN−/− hearts, no prolongation of FP duration was observed. (83 ± 1 ms, n = 49 vs. 81 ± 3 ms, n = 18).
Conclusion: Our study supports the hypothesis that PLN is a key player in the electrophysiological remodeling of mechanically unloaded hearts. PLN deficiency leads to a resolution of functional impairments of excitation conduction and therefore holds the potential for future therapeutic approaches.