Institute of Molecular Cardiology, Department of Medicine, University of Louisville, KY, USA; Department of Physiology and Biophysics, University of Louisville, KY, USA.
Institute of Molecular Cardiology, Department of Medicine, University of Louisville, KY, USA.
Biochim Biophys Acta Mol Basis Dis. 2021 May 1;1867(5):166080. doi: 10.1016/j.bbadis.2021.166080. Epub 2021 Jan 21.
The peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) regulates metabolism and is essential for normal cardiac function. Its activity is suppressed during pressure overload induced cardiac hypertrophy and such suppression at least partially contributes to the associated morbidity. The O-linked β-N-acetylglucosamine post-translational modification (O-GlcNAc) of proteins is a glucose-derived metabolic signal. The relationship between O-GlcNAc, and PGC-1α activity in cardiac hypertrophy is unknown. We hypothesized that hypertrophy-induced suppression of PGC-1α was at least partially regulated by O-GlcNAc signaling. Treatment of neonatal rat cardiac myocytes with phenylephrine (an inducer of cardiomyocyte hypertrophy) significantly enhanced global O-GlcNAc signaling. Quantitative real-time PCR analysis revealed a downregulation of PGC-1α with concomitant suppression of fatty acid oxidation/mitochondrial genes. Transverse aortic constriction in mice decreased the basal expression of PGC-1α and its downstream genes. Reduction of O-GlcNAc signaling alleviated suppression of PGC-1α and most of its downstream genes. Interestingly, augmentation of O-GlcNAc signaling with glucosamine or PUGNAC (a O-GlcNAcase inhibitor) reduced glucose starvation-induced PGC-1α upregulation even in the absence of hypertrophy. Finally, we found that PGC-1α itself is O-GlcNAcylated. Together, these results reveal the recruitment of O-GlcNAc signaling as a potentially novel regulator of PGC-1α activity during cardiac hypertrophy. Furthermore, O-GlcNAc signaling may mediate constitutive suppression of PGC-1α activity in the heart. Such findings illuminate new possibilities regarding the inter-regulation of O-GlcNAc signaling and also may have some implications for metabolic dysregulation during cardiac diseases.
过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）调节代谢，是正常心脏功能所必需的。在压力超负荷诱导的心肌肥厚中，其活性受到抑制，这种抑制至少部分导致了相关的发病率。蛋白质的 O-链接β-N-乙酰氨基葡萄糖基化（O-GlcNAc）是一种葡萄糖衍生的代谢信号。O-GlcNAc 与心肌肥厚中 PGC-1α 活性之间的关系尚不清楚。我们假设，至少部分通过 O-GlcNAc 信号来调节肥大诱导的 PGC-1α 抑制。用苯肾上腺素（一种诱导心肌细胞肥大的诱导剂）处理新生大鼠心肌细胞，显著增强了全局 O-GlcNAc 信号。定量实时 PCR 分析显示 PGC-1α 下调，同时伴随着脂肪酸氧化/线粒体基因的抑制。在小鼠中横主动脉缩窄降低了 PGC-1α 及其下游基因的基础表达。减少 O-GlcNAc 信号减轻了 PGC-1α 及其大部分下游基因的抑制。有趣的是，用葡萄糖胺或 PUGNAC（O-GlcNAcase 抑制剂）增加 O-GlcNAc 信号甚至在没有肥大的情况下，也会减少葡萄糖饥饿诱导的 PGC-1α 上调。最后，我们发现 PGC-1α 本身被 O-GlcNAc 化。总之，这些结果揭示了 O-GlcNAc 信号的招募作为心肌肥厚期间 PGC-1α 活性的一种潜在的新型调节剂。此外，O-GlcNAc 信号可能介导 PGC-1α 活性在心脏中的组成性抑制。这些发现阐明了 O-GlcNAc 信号的相互调节的新可能性，并且可能对心脏疾病期间的代谢失调有一些影响。
