Alterations of sarcoplasmic reticulum-mediated Ca2+ uptake in a model of premature ventricular contraction (PVC)-induced cardiomyopathy.
Alterations of sarcoplasmic reticulum-mediated Ca2+ uptake in a model of premature ventricular contraction (PVC)-induced cardiomyopathy.
复制标题
室性早搏 (PVC) 诱发的心肌病模型中肌浆网介导的 Ca2 摄取的变化。
DOI：
10.1007/s11010-022-04605-y
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发表时间：
2023
影响因子：
4.3
通讯作者：
Eltit,JoseM
中科院分区：
文献类型：
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作者：
Balderas-Villalobos,Jaime;Medina-Contreras,JML;Lynch,Christopher;Kabadi,Rajiv;Ramirez,RafaelJ;Tan,AlexY;Kaszala,Karoly;Samsó,Montserrat;Huizar,JoseF;Eltit,JoseM
室性早搏（PVC）是总体人群中最常见的室性心律失常。已知PVC通过期外收缩后增强现象急性增强收缩力，但随着时间的推移，持续性PVC促进PVC诱导的心肌病（PVC-CM），其特征在于左心室（LV）射血分数降低。肌细胞中的Ca 2+循环命令肌肉收缩，并且在此过程中，SERCA 2导致Ca 2+再摄取到肌浆网（SR）中，从而形成胞质Ca 2+信号衰减和肌肉松弛。改变的Ca 2+再摄取可导致PVC-CM中观察到的收缩功能障碍。为了更好地理解使用我们的PVC-CM模型（犬具有50%PVC负荷12周）的Ca 2+处理，通过测量Ca 2+动力学和分析蛋白质表达来研究SR-Ca 2+再摄取。电起搏心肌细胞中Ca 2+再摄取的动力学分析显示，与完整分离的心肌细胞中的假手术相比，PVC-CM延迟约21 ms，沿着在透化心肌细胞中评估的SERCA 2活性降低约13%。尽管使用分层统计，这些趋势在组间无统计学显著性，但PVC-CM与Sham肌细胞相比，收缩后肌细胞的舒张显著较慢。蛋白质印迹分析表明，PVC-CM样品与假手术相比，SERCA 2表达减少22%，受磷蛋白（PLN）表达增加23%，PLN磷酸化减少50%。模拟SR-Ca 2+再摄取减少20%的计算分析导致Ca 2+信号衰减延迟约22 ms，与上述实验结果一致。总之，上述SERCA 2和PLB改变对PVC-CM中观察到的功能适应具有适度的贡献。
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. Ca2+cycling in myocytes commands muscle contraction and in this process, SERCA2 leads the Ca2+reuptake into the sarcoplasmic reticulum (SR) shaping cytosolic Ca2+signal decay and muscle relaxation. Altered Ca2+reuptake can contribute to the contractile dysfunction observed in PVC-CM. To better understand Ca2+handling using our PVC-CM model (canines with 50% PVC burden for 12 weeks), SR-Ca2+reuptake was investigated by measuring Ca2+dynamics and analyzing protein expression. Kinetic analysis of Ca2+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-CMvsSham 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 samplesvsSham. Computational analysis simulating a 20% decrease in SR-Ca2+reuptake resulted in a ~ 22 ms delay in Ca2+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.