Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy
Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy
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DOI：
10.1161/01.res.0000109415.17511.18
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发表时间：
2004-01-09
影响因子：
20.1
通讯作者：
Molkentin, JD
中科院分区：
文献类型：
--
作者：
Wilkins, BJ;Dai, YS;Molkentin, JD
钙调磷酸酶（PP 2B）是一种钙/钙调蛋白激活的丝氨酸-苏氨酸磷酸酶，其通过活化T细胞核因子（NFAT）转录因子的去磷酸化和易位将信号传递到细胞核。尽管钙调神经磷酸酶-NFAT信号转导与调节心肌肥厚性生长有关，但关于其在维持与引发肥厚中的作用、其在病理性与生理性肥厚中的作用以及其在心力衰竭中的作用仍存在相当大的争议。为了解决这些问题，产生并表征了NFAT-荧光素酶报告基因转基因小鼠。这些小鼠在心脏中显示出稳健的和钙调神经磷酸酶特异性的激活，这被环孢菌素A抑制。在成人心脏中，NFAT-荧光素酶活性在由压力超负荷诱导的病理性心脏肥大的整个8周内以延迟但持续的方式上调，或者在心肌梗死诱导的心力衰竭后更显著地上调。相比之下，在两个单独的运动训练模型中产生的生理性肥大在多个时间点未能在心脏中显示出显著的钙调神经磷酸酶-NFAT偶联，尽管心脏与体重比可测量地增加。此外，生长激素-胰岛素样生长因子-1（GH-IGF-1）刺激肥大未能激活心脏或培养物中的钙调神经磷酸酶NFAT信号传导，尽管肥大、Akt激活和p70 S6 K激活。钙调磷酸酶Abeta基因靶向小鼠在GH-IGF-1输注后也显示出正常的肥大反应。最后，与压力超负荷动物相比，运动或GH-IGF-1诱导的心脏生长未能诱导肥大标志物基因表达。虽然NFAT-荧光素酶活性和病理性肥大之间的直接因果关系没有得到证实，我们的研究结果支持这一假设，即可分离的信号通路调节心肌的病理性与生理性肥大生长，钙调神经磷酸酶-NFAT可能发挥更专门的调节作用，适应不良肥大和心力衰竭。
Calcineurin (PP2B) is a calcium/calmodulin-activated, serine-threonine phosphatase that transmits signals to the nucleus through the dephosphorylation and translocation of nuclear factor of activated T cell ( NFAT) transcription factors. Whereas calcineurin-NFAT signaling has been implicated in regulating the hypertrophic growth of the myocardium, considerable controversy persists as to its role in maintaining versus initiating hypertrophy, its role in pathological versus physiological hypertrophy, and its role in heart failure. To address these issues, NFAT-luciferase reporter transgenic mice were generated and characterized. These mice showed robust and calcineurin-specific activation in the heart that was inhibited with cyclosporin A. In the adult heart, NFAT-luciferase activity was upregulated in a delayed, but sustained manner throughout eight weeks of pathological cardiac hypertrophy induced by pressure-overload, or more dramatically following myocardial infarction-induced heart failure. In contrast, physiological hypertrophy as produced in two separate models of exercise training failed to show significant calcineurin-NFAT coupling in the heart at multiple time points, despite measurable increases in heart to body weight ratios. Moreover, stimulation of hypertrophy with growth hormone-insulin-like growth factor-1 (GH-IGF-1) failed to activate calcineurin NFAT signaling in the heart or in culture, despite hypertrophy, activation of Akt, and activation of p70 S6K. Calcineurin Abeta gene-targeted mice also showed a normal hypertrophic response after GH-IGF-1 infusion. Lastly, exercise- or GH-IGF-1-induced cardiac growth failed to show induction of hypertrophic marker gene expression compared with pressure-overloaded animals. Although a direct cause-and-effect relationship between NFAT-luciferase activity and pathological hypertrophy was not proven here, our results support the hypothesis that separable signaling pathways regulate pathological versus physiological hypertrophic growth of the myocardium, with calcineurin-NFAT potentially serving a regulatory role that is more specialized for maladaptive hypertrophy and heart failure.