Activation of PKCα participates in the reduction of Ikur in atrial myocytes induced by tumour necrosis factor‐α
Activation of PKCα participates in the reduction of Ikur in atrial myocytes induced by tumour necrosis factor‐α
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DOI：
10.1111/1440-1681.13407
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发表时间：
2020-09
影响因子：
2.9
通讯作者：
Hui-Shan Zhou;D. Peng;Yingyu Lai;Qian Li;Jun-Fei Zhao;C. Deng;Hui Yang;Teng Li;Zhaoyu Wang;Yuwen Xu;Yu-mei Xue;Shu-lin Wu;Hui-ming Guo;F. Rao
中科院分区：
文献类型：
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作者：
Hui-Shan Zhou;D. Peng;Yingyu Lai;Qian Li;Jun-Fei Zhao;C. Deng;Hui Yang;Teng Li;Zhaoyu Wang;Yuwen Xu;Yu-mei Xue;Shu-lin Wu;Hui-ming Guo;F. Rao
心房特异性超快速延迟整流钾电流（Ikur）在房颤（AF）的进展中起着重要作用。由于已知炎症会导致AF发作，因此我们旨在研究肿瘤坏死因子-α（TNF-α）是否在调节Ikur和相关的潜在信号通路中发挥作用。采用全细胞膜片钳和生化分析研究了Ikur在窦性心律（SR）或AF患者左心房附件（LAA）的肌细胞和组织以及大鼠心肌细胞（H9 c2细胞）和小鼠心房肌细胞（HL-1细胞）中的调节和表达。与SR对照组相比，AF患者心房肌细胞的Ikur电流密度显著降低。AF患者中Kv1.5蛋白水平降低伴随TNF-α表达增加和蛋白激酶C（PKC）α激活。TNF-α剂量依赖性地降低了H9 c2细胞和HL-1细胞中Kv1.5的Ikur和蛋白表达，但不降低Kv3.1b的表达。TNF-α还增加PKCα的活性。特异性PKCα抑制剂Gö 6976可减轻TNF-α诱导的Ikur降低，但不能减轻Kv1.5蛋白的降低。TNF-α可能通过激活PKCα抑制心房肌细胞的Ikur而参与AF相关的电重构。
The atrial‐specific ultra‐rapid delayed rectifier K+ current (Ikur) plays an important role in the progression of atrial fibrillation (AF). Because inflammation is known to lead to the onset of AF, we aimed to investigate whether tumour necrosis factor‐α (TNF‐α) played a role in regulating Ikur and the potential signalling pathways involved. Whole‐cell patch‐clamp and biochemical assays were used to study the regulation and expression of Ikur in myocytes and in tissues from left atrial appendages (LAAs) obtained from patients with sinus rhythm (SR) or AF, as well as in rat cardiomyocytes (H9c2 cells) and mouse atrial myocytes (HL‐1 cells). Ikur current density was markedly reduced in atrial myocytes from AF patients compared with SR controls. Reduction of Kv1.5 protein levels was accompanied by increased expression of TNF‐α and protein kinase C (PKC)α activation in AF patients. Treatment with TNF‐α dose‐dependently reduced Ikur and protein expression of Kv1.5 but not Kv3.1b in H9c2 cells and HL‐1 cells. TNF‐α also increased activity of PKCα. Specific PKCα inhibitor Gö6976 alleviated the reduction in Ikur induced by TNF‐α, but not the reduction in Kv1.5 protein. TNF‐α was involved in the electrical remodelling associated with AF, probably by depressing Ikur in atrial myocytes via activation of PKCα.