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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >TRPC channels are necessary mediators of pathologic cardiac hypertrophy
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TRPC channels are necessary mediators of pathologic cardiac hypertrophy

机译：TRPC通道是病理性心肌肥大的必要介质

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摘要

Pathologic hypertrophy of the heart is regulated through membrane-bound receptors and intracellular signaling pathways that function, in part, by altering Ca~(2+) handling and Ca~(2+)-dependent signaling effectors. Transient receptor potential canonical (TRPC) channels are important mediators of Ca~(2+)-dependent signal transduction that can sense stretch or activation of membrane-bound receptors. Here we generated cardiac-specific transgenic mice that express dominant-negative (dn) TRPC3, dnTRPC6, or dnTRPC4 toward blocking the activity of the TRPC3/6/7 or TRPC1/4/5 subfamily of channels in the heart. Remarkably, all three dn transgenic strategies attenuated the cardiac hyper-trophic response following either neuroendocrine agonist infusion or pressure-overload stimulation. dnTRPC transgenic mice also were partially protected from loss of cardiac functional performance following long-term pressure-overload stimulation. Importantly, adult myocytes isolated from hypertrophic WT hearts showed a unique Ca~(2+) influx activity under store-depleted conditions that was not observed in myocytes from hypertrophied dnTRPC3, dnTRPC6, or dnTRPC4 hearts. Moreover, dnTRPC4 inhibited the activity of the TRPC3/6/7 subfamily in the heart, suggesting that these two subfamilies function in coordinated complexes. Mechanistically, inhibition of TRPC channels in transgenic mice or in cultured neonatal myocytes significantly reduced activity in the calcineurin-nuclear factor of activated T cells (NFAT), a known Ca~(2+)-dependent hypertrophy-inducing pathway. Thus, TRPC channels are necessary mediators of pathologic cardiac hypertrophy, in part through a calcineurin-NFAT signaling pathway.
机译：心脏的病理性肥大是通过膜结合受体和细胞内信号通路来调节的，这些通路部分地通过改变Ca〜（2+）处理和Ca〜（2+）依赖的信号传导因子来发挥作用。瞬态受体电位规范（TRPC）通道是依赖Ca〜（2+）的信号转导的重要介体，可以感知膜结合受体的伸展或激活。在这里，我们生成了心脏特异性转基因小鼠，它们表达显性阴性（dn）TRPC3，dnTRPC6或dnTRPC4，以阻断心脏通道的TRPC3 / 6/7或TRPC1 / 4/5的活动。值得注意的是，在神经内分泌激动剂输注或压力超负荷刺激后，所有三种dn转基因策略均减弱了心肌肥厚反应。长期压力超负荷刺激后，dnTRPC转基因小鼠也受到部分保护，免受心脏功能丧失的影响。重要的是，从肥大的WT心脏分离的成年心肌细胞在储存耗尽的条件下表现出独特的Ca〜（2+）流入活性，而肥大的dnTRPC3，dnTRPC6或dnTRPC4的心肌细胞中未观察到这种活性。此外，dnTRPC4抑制了心脏中TRPC3 / 6/7亚家族的活性，表明这两个亚家族在协调复合物中起作用。从机制上讲，抑制转基因小鼠或培养的新生儿心肌细胞中的TRPC通道会显着降低活化T细胞的钙调神经磷酸酶核因子（NFAT）的活性，这是一种已知的Ca〜（2+）依赖性肥大诱导途径。因此，TRPC通道部分地通过钙调神经磷酸酶-NFAT信号通路是病理性心脏肥大的必要介质。

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  • 作者

    Xu Wu; Petra Eder; Baojun Chang; Jeffery D. Molkentin;

  • 作者单位

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229;

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229;

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229;

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229 Howard Hughes Medical Institute, Cincinnati, OH 45229;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    calcium; heart; signaling; calcineurin;

    机译：钙;心;发信号钙调神经磷酸酶;

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