Reduction of Ito causes hypertrophy in neonatal rat ventricular myocytes
Reduction of Ito causes hypertrophy in neonatal rat ventricular myocytes
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DOI：
10.1161/01.res.0000012223.86441.a1
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发表时间：
2002-03-22
影响因子：
20.1
通讯作者：
Backx, PH
中科院分区：
文献类型：
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作者：
Kassiri, Z;Zobel, C;Backx, PH
由于 K-v4.2 和 K-v4.3 基因表达减少，导致动作电位持续时间 (APD) 延长和瞬时外向 K+ 电流 (I,,) 减少，这在心脏病中常见。我们发现，使用细胞膜电容和 3 H-亮氨酸摄取测量，用心脏 I-to 阻断剂 Heteropoda Toxin(3) 处理培养的新生大鼠心室肌细胞会诱导肥大。为了剖析特定 I-to 编码基因在肥大中的作用，通过过表达突变体显性失活 (DN) trariggenes 选择性地减少 I-to。通过过度表达 DN K-v1.4 (Kv1.4N) 或 DN K-v1.2（Kv4.2N 或 K(v4.2)W362F），I-to 振幅同样降低（约 50%），但只有 DN K,4 2 延长 APD 持续时间（1 Hz）并诱导肌细胞肥大。通过将野生型 K-v4.2 通道 (Kv4.2F) 与 DN K-v4.2 基因共表达来防止这种肥大，表明肥大是由于 I-to 减少而不是转基因过度表达的非特异性影响。基于 K-v4.x 的 I-to 减少引起的肥大与钙依赖性磷酸酶、钙调磷酸酶活性的增加有关，并且可以通过与 Ad-CAIN（一种特定的钙调磷酸酶抑制剂）共感染来预防。通过用维拉帕米或高 [K-=](0) 阻断 Ca2+ 进入和兴奋性，可以防止 Kv4.2N 感染诱导的肥大和钙调磷酸酶激活。我们的研究表明，基于 K-v4.2/3 的 I-to 的减少通过激活钙调蛋白在肥大信号传导中发挥作用。
Prolonged action potential duration (APD) and decreased transient outward K+ current (I,,) as a result of decreased expression of K-v4.2 and K-v4.3 genes are commonly observed in heart disease. We found that treatment of cultured neonatal rat ventricular myocytes with Heteropoda Toxin(3), a blocker of cardiac I-to induced hypertrophy as measured using cell membrane capacitance and 3 H-leucine uptake. To dissect the role of specific I-to-encoding genes in hypertrophy, I-to was selectively reduced by overexpressing mutant dominant-negative (DN) trariggenes. I-to amplitude was reduced equally (by about 50%) by overexpression of DN K-v1.4 (Kv1.4N) or DN K-v1.2 (either Kv4.2N or K(v4.2)W362F), but only DN K,4 2 prolonged APD duration (at 1 Hz) and induced myocyte hypertrophy. This hypertrophy was prevented by coexpressing wild-type K-v4.2 channels (Kv4.2F) with the DN K-v4.2 genes, suggesting the hypertrophy is due to I-to reduction and not nonspecific effects of transgene overexpression. The hypertrophy caused by reductions of K-v4.x-based I-to was associated with increased activity of the calcium-dependent phosphatase, calcinceurin, and could be prevented by coinfection with Ad-CAIN, a specific calcineurin inhibitor. The hypertrophy and calcineurin activation induced by Kv4.2N infection were prevented by blocking Ca2+ entry and excitability with verapamil or high [K-=](0). Our studies suggest that reductions of K-v4.2/3-based I-to play a role in hypertrophy signaling by activation of calcincurin.