Alterations of sarcoplasmic reticulum-mediated Ca.sup.2+ uptake in a model of premature ventricular contraction -induced cardiomyopathy

Premature ventricular contractions (PVCs) are the most frequent ventricular arrhythmias in the overall population. PVCs are known to acutely enhance contractility by the post-extrasystolic potentiation phenomenon, but over time persistent PVCs promote PVC-induced cardiomyopathy (PVC-CM), characteriz...

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Bibliographic Details
Published in:Molecular and cellular biochemistry 2023-07, Vol.478 (7), p.1447
Main Authors: Balderas-Villalobos, Jaime, Medina-Contreras, J. M. L, Lynch, Christopher, Kabadi, Rajiv, Ramirez, Rafael J, Tan, Alex Y, Kaszala, Karoly
Format: Article
Language:English
Subjects:
Analysis
Arrhythmia
Cardiomyopathy
Heart diseases
Polyvinyl chloride
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Summary:Premature ventricular contractions (PVCs) are the most frequent ventricular arrhythmias in the overall population. PVCs are known to acutely enhance contractility by the post-extrasystolic potentiation phenomenon, but over time persistent PVCs promote PVC-induced cardiomyopathy (PVC-CM), characterized by a reduction of the left ventricular (LV) ejection fraction. Ca.sup.2+ cycling in myocytes commands muscle contraction and in this process, SERCA2 leads the Ca.sup.2+ reuptake into the sarcoplasmic reticulum (SR) shaping cytosolic Ca.sup.2+ signal decay and muscle relaxation. Altered Ca.sup.2+ reuptake can contribute to the contractile dysfunction observed in PVC-CM. To better understand Ca.sup.2+ handling using our PVC-CM model (canines with 50% PVC burden for 12 weeks), SR-Ca.sup.2+ reuptake was investigated by measuring Ca.sup.2+ dynamics and analyzing protein expression. Kinetic analysis of Ca.sup.2+ reuptake in electrically paced myocytes showed a ~ 21 ms delay in PVC-CM compared to Sham in intact isolated myocytes, along with a ~ 13% reduction in SERCA2 activity assessed in permeabilized myocytes. Although these trends were not statistically significant between groups using hierarchical statistics, relaxation of myocytes following contraction was significantly slower in PVC-CM vs Sham myocytes. Western blot analyses indicate a 22% reduction in SERCA2 expression, a 23% increase in phospholamban (PLN) expression, and a 50% reduction in PLN phosphorylation in PVC-CM samples vs Sham. Computational analysis simulating a 20% decrease in SR-Ca.sup.2+ reuptake resulted in a ~ 22 ms delay in Ca.sup.2+ signal decay, consistent with the experimental result described above. In conclusion, SERCA2 and PLB alterations described above have a modest contribution to functional adaptations observed in PVC-CM.
ISSN:0300-8177
1573-4919
DOI:10.1007/s11010-022-04605-y