NFATc3 and NFATc4 are required for cardiac development and mitochondrial function
NFATc3 and NFATc4 are required for cardiac development and mitochondrial function
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DOI：
10.1161/01.res.0000077045.84609.9f
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发表时间：
2003-06-27
影响因子：
20.1
通讯作者：
Yutzey, KE
中科院分区：
文献类型：
--
作者：
Bushdid, PB;Osinska, H;Yutzey, KE
激活的T细胞核因子(NFAT)家族转录因子的激活与成人心肌和骨骼肌的基因表达和肌细胞功能的变化有关。然而，NFATs在正常胚胎心脏发育中的作用还没有得到很好的描述。在这份报告中，研究了NFATc3和NFATc4在NFATc3和NFATc4基因定向干扰的小鼠胚胎心脏发育中的作用。NFATC3(-/-)NFATC4(-/-)小鼠在胚胎10.5天后表现出胚胎致死性，并出现脑室变薄，心包积液，以及心室肌细胞增殖减少。心肌线粒体肿胀，伴有异常的嵴，提示代谢衰竭，但细胞凋亡的特征不明显。此外，NFATC3(-/-)NFATC4(-/-)心肌细胞呼吸链复合体II和IV的酶活性和线粒体氧化活性降低。在NFATc3(-/-)NFATC4(-/-)胚胎中心脏特异性表达NFATc4可将胚胎存活率延长至胚胎第12天，并保护心室肌细胞的增殖、致密区密度和小梁形成。挽救的胚胎也保持了心肌线粒体的超微结构和复合II酶的活性。总之，这些数据支持这样的假设，即心脏中NFAT活性的丧失会导致心脏形态发生和功能所需的线粒体能量代谢不足。
Activation of the nuclear factor of activated T-cell ( NFAT) family of transcription factors is associated with changes in gene expression and myocyte function in adult cardiac and skeletal muscle. However, the role of NFATs in normal embryonic heart development is not well characterized. In this report, the function of NFATc3 and NFATc4 in embryonic heart development was examined in mice with targeted disruption of both nfatc3 and nfatc4 genes. The nfatc3(-/-) nfatc4(-/-) mice demonstrate embryonic lethality after embryonic day 10.5 and have thin ventricles, pericardial effusion, and a reduction in ventricular myocyte proliferation. Cardiac mitochondria are swollen with abnormal cristae, indicative of metabolic failure, but hallmarks of apoptosis are not evident. Furthermore, enzymatic activity of complex II and IV of the respiratory chain and mitochondrial oxidative activity are reduced in nfatc3(-/-) nfatc4(-/-) cardiomyocytes. Cardiac-specific expression of constitutively active NFATc4 in nfatc3(-/-) nfatc4(-/-) embryos prolongs embryonic viability to embryonic day 12 and preserves ventricular myocyte proliferation, compact zone density, and trabecular formation. The rescued embryos also maintain cardiac mitochondrial ultrastructure and complex II enzyme activity. Together, these data support the hypothesis that loss of NFAT activity in the heart results in a deficiency in mitochondrial energy metabolism required for cardiac morphogenesis and function.