Department of Medicine, Institute of Molecular Cardiology, Louisville, KY 40202, USA.
Am J Physiol Heart Circ Physiol. 2012 May 15;302(10):H2122-30. doi: 10.1152/ajpheart.00775.2011. Epub 2012 Mar 9.
The regulation of cardiomyocyte hypertrophy is a complex interplay among many known and unknown processes. One specific pathway involves the phosphatase calcineurin, which regulates nuclear translocation of the essential cardiac hypertrophy transcription factor, nuclear factor of activated T-cells (NFAT). Although metabolic dysregulation is frequently described during cardiac hypertrophy, limited insights exist regarding various accessory pathways. One metabolically derived signal, beta-O-linked N-acetylglucosamine (O-GlcNAc), has emerged as a highly dynamic posttranslational modification of serine and threonine residues regulating physiological and stress processes. Given the metabolic dysregulation during hypertrophy, we hypothesized that NFAT activation is dependent on O-GlcNAc signaling. Pressure overload-induced hypertrophy (via transverse aortic constriction) in mice or treatment of neonatal rat cardiac myocytes with phenylephrine significantly enhanced global O-GlcNAc signaling. NFAT-luciferase reporter activity revealed O-GlcNAc-dependent NFAT activation during hypertrophy. Reversal of enhanced O-GlcNAc signaling blunted cardiomyocyte NFAT-induced changes during hypertrophy. Taken together, these results demonstrate a critical role of O-GlcNAc signaling in NFAT activation during hypertrophy and provide evidence that O-GlcNAc signaling is coordinated with the onset and progression of cardiac hypertrophy. This represents a potentially significant and novel mechanism of cardiac hypertrophy, which may be of particular interest in future in vivo studies of hypertrophy.
心肌细胞肥大的调节是许多已知和未知过程之间复杂的相互作用。一个特定的途径涉及磷酸酶钙调神经磷酸酶，它调节激活 T 细胞核因子（NFAT）这一心脏肥大转录因子的核易位。尽管在心脏肥大过程中经常描述代谢失调，但对于各种辅助途径的了解有限。一种代谢衍生的信号，β-O-连接的 N-乙酰氨基葡萄糖（O-GlcNAc），已成为调节生理和应激过程的丝氨酸和苏氨酸残基的高度动态的翻译后修饰。鉴于肥大过程中的代谢失调，我们假设 NFAT 的激活依赖于 O-GlcNAc 信号。通过横主动脉缩窄（transverse aortic constriction）诱导的小鼠心脏肥厚或苯肾上腺素处理新生大鼠心肌细胞显著增强了全局 O-GlcNAc 信号。NFAT-荧光素酶报告基因活性显示 O-GlcNAc 依赖性 NFAT 在肥大过程中的激活。增强的 O-GlcNAc 信号的逆转减弱了肥大过程中心肌细胞 NFAT 诱导的变化。综上所述，这些结果表明 O-GlcNAc 信号在 NFAT 激活过程中在肥大过程中起着关键作用，并为 O-GlcNAc 信号与心脏肥大的起始和进展协调一致提供了证据。这代表了一种潜在的重要的心脏肥大新机制，在未来的心脏肥大的体内研究中可能具有特别的意义。
