PICOT attenuates cardiac hypertrophy by disrupting calcineurin - NFAT signaling
PICOT attenuates cardiac hypertrophy by disrupting calcineurin - NFAT signaling
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DOI：
10.1161/circresaha.107.165985
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发表时间：
2008-03-28
影响因子：
20.1
通讯作者：
Park, Woo Jin
中科院分区：
文献类型：
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作者：
Jeong, Dongtak;Kim, Ji Myoung;Park, Woo Jin
PICOT（硫氧还蛋白的蛋白激酶C相互作用表兄弟）以前被证明可以抑制压力超负荷诱导的心脏肥大，同时增加心室功能和心肌细胞收缩力。谷胱甘肽S-转移酶下拉实验和质谱的组合分析使我们能够确定PICOT通过其羧基末端半（PICOT-C）与肌肉LIM蛋白（MLP）直接相互作用。还表明PICOT与MLP在Z盘中共定位。已知MLP在将钙调磷酸酶锚定到肌节中的Z盘中起作用，这对于钙调磷酸酶- NFAT（活化T细胞的核因子）信号传导是关键的。因此，我们认为PICOT可能通过与MLP的相互作用影响钙调神经磷酸酶- NFAT信号转导。与这一假设相一致，PICOT，或更具体地PICOT-C，消除了新生心肌细胞中苯肾上腺素诱导的钙调磷酸酶活性增加、NFAT去磷酸化/核转位和NFAT依赖性转录激活。此外，压力超负荷诱导的NFAT靶基因上调在PICOT过表达转基因小鼠的心脏中显著减少。PICOT以剂量依赖性方式干扰MLP -钙调磷酸酶相互作用。此外，在PICOT转基因小鼠的心脏中，钙调神经磷酸酶从Z盘被置换，伴随着钙调神经磷酸酶和MLP之间的相互作用被废除。MLP的补充恢复了肥大反应和PICOT抑制的钙调磷酸酶活性的增加，苯肾上腺素处理的心肌细胞。最后，PICOT-C抑制心脏肥大的程度与全长PICOT相当。综上所述，这些数据表明PICOT主要通过破坏MLP -钙调磷酸酶相互作用负调节钙调磷酸酶- NFAT信号传导来抑制心脏肥大。
PICOT ( protein kinase C-interacting cousin of thioredoxin) was previously shown to inhibit pressure overload-induced cardiac hypertrophy, concomitant with an increase in ventricular function and cardiomyocyte contractility. The combined analyses of glutathione S-transferase pull-down experiments and mass spectrometry enabled us to determine that PICOT directly interacts with muscle LIM protein (MLP) via its carboxyl-terminal half ( PICOT-C). It was also shown that PICOT colocalizes with MLP in the Z-disc. MLP is known to play a role in anchoring calcineurin to the Z-disc in the sarcomere, which is critical for calcineurin - NFAT ( nuclear factor of activated T cells) signaling. We, therefore, suggested that PICOT may affect calcineurin - NFAT signaling through its interaction with MLP. Consistent with this hypothesis, PICOT, or more specifically PICOT-C, abrogated phenylephrine-induced increases in calcineurin phosphatase activity, NFAT dephosphorylation/nuclear translocation, and NFAT-dependent transcriptional activation in neonatal cardiomyocytes. In addition, pressure overload - induced upregulation of NFAT target genes was significantly diminished in the hearts of PICOT-overexpressing transgenic mice. PICOT interfered with MLP - calcineurin interactions in a dose-dependent manner. Moreover, calcineurin was displaced from the Z-disc, concomitant with an abrogated interaction between calcineurin and MLP, in the hearts of PICOT transgenic mice. Replenishment of MLP restored the hypertrophic responses and the increase in calcineurin phosphatase activity that was inhibited by PICOT in phenylephrine-treated cardiomyocytes. Finally, PICOT-C inhibited cardiac hypertrophy to an extent that was comparable to that of full-length PICOT. Taken together, these data suggest that PICOT inhibits cardiac hypertrophy largely by negatively regulating calcineurin - NFAT signaling via disruption of the MLP - calcineurin interaction.