TRPC channels are necessary mediators of pathologic cardiac hypertrophy
TRPC channels are necessary mediators of pathologic cardiac hypertrophy
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DOI：
10.1073/pnas.1001825107
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发表时间：
2010-04-13
影响因子：
11.1
通讯作者：
Molkentin, Jeffery D.
中科院分区：
文献类型：
--
作者：
Wu, Xu;Eder, Petra;Molkentin, Jeffery D.
心脏的病理性肥大是通过膜结合受体和细胞内信号传导途径来调节的，这些信号传导途径在一定程度上是通过改变 Ca2+ 处理和 Ca2+ 依赖性信号传导效应器来发挥作用的。瞬时受体电位规范 (TRPC) 通道是 Ca2+ 依赖性信号转导的重要介质，可以感知膜结合受体的拉伸或激活。在这里，我们生成了表达显性失活（dn）TRPC3、dnTRPC6或dnTRPC4的心脏特异性转基因小鼠，以阻断心脏中TRPC3/6/7或TRPC1/4/5通道亚家族的活性。值得注意的是，所有三种 dn 转基因策略均减弱了神经内分泌激动剂输注或压力超负荷刺激后的心脏肥大反应。 dnTRPC 转基因小鼠在长期压力超负荷刺激后也能部分免受心脏功能丧失的影响。重要的是，从肥大的 WT 心脏分离的成体肌细胞在储备耗尽的条件下表现出独特的 Ca2+ 流入活性，而在肥大的 dnTRPC3、dnTRPC6 或 dnTRPC4 心脏的肌细胞中未观察到这种活性。此外，dnTRPC4 抑制心脏中 TRPC3/6/7 亚家族的活性，表明这两个亚家族在协调复合体中发挥作用。从机制上讲，抑制转基因小鼠或培养的新生肌细胞中的 TRPC 通道可显着降低活化 T 细胞的钙调磷酸酶核因子 (NFAT) 的活性，这是一种已知的 Ca2+ 依赖性肥大诱导途径。因此，TRPC 通道是病理性心脏肥大的必要介质，部分通过钙调神经磷酸酶-NFAT 信号通路实现。
Pathologic hypertrophy of the heart is regulated through membrane-bound receptors and intracellular signaling pathways that function, in part, by altering Ca2+ handling and Ca2+-dependent signaling effectors. Transient receptor potential canonical (TRPC) channels are important mediators of Ca2+-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 hypertrophic response following either neuroendocrine agonist infusion or pressure-overload stimulation. dnTRPC transgenicmice 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 Ca2+ 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 Ca2+-dependent hypertrophy-inducing pathway. Thus, TRPC channels are necessary mediators of pathologic cardiac hypertrophy, in part through a calcineurin-NFAT signaling pathway.