Cardiac hypertrophy drives PGC-1α suppression associated with enhanced O-glycosylation
Cardiac hypertrophy drives PGC-1α suppression associated with enhanced O-glycosylation
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DOI：
10.1016/j.bbadis.2021.166080
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发表时间：
2021-01-25
影响因子：
6.2
通讯作者：
Facundo, Heberty T.
中科院分区：
文献类型：
--
作者：
Brainard, Robert E.;Facundo, Heberty T.
过氧化物酶体增殖物激活受体-γ共激活因子-1 α（PGC-1 α）调节代谢，对正常心脏功能至关重要。其活性在压力超负荷诱导的心脏肥大期间受到抑制，并且这种抑制至少部分促成相关的发病率。蛋白质的O-连接β-N乙酰葡糖胺翻译后修饰（O-GlcNAc）是葡萄糖衍生的代谢信号。心肌肥大中O-GlcNAc和PGC-1 α活性之间的关系尚不清楚。我们假设肥大诱导的PGC-1 α抑制至少部分受O-GlcNAc信号调节。用苯异黄酮（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信号传导。定量实时PCR分析显示PGC-1 α下调伴随着脂肪酸氧化/线粒体基因的抑制。小鼠的横向主动脉缩窄降低了PGC-1 α及其下游基因的基础表达。OGlcNAc信号传导的减少缓解了PGC-1 α及其大多数下游基因的抑制。有趣的是，即使在没有肥大的情况下，用葡糖胺或PUGNAC（O-GlcNAc酶抑制剂）增强O-GlcNAc信号传导也减少了葡萄糖饥饿诱导的PGC-1 α上调。最后，我们发现PGC-1 α本身是O-GlcNAc酰化的。总之，这些结果揭示了O-GlcNAc信号传导作为心脏肥大期间PGC-1 α活性的潜在新型调节剂的募集。此外，O-GlcNAc信号传导可介导心脏中PGC-1 α活性的组成性抑制。这些发现阐明了O-GlcNAc信号相互调节的新可能性，也可能对心脏疾病期间的代谢失调产生一些影响。
The peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) 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 beta-Nacetylglucosamine post-translational modification (O-GlcNAc) of proteins is a glucose-derived metabolic signal. The relationship between O-GlcNAc, and PGC-1 alpha activity in cardiac hypertrophy is unknown. We hypothesized that hypertrophy-induced suppression of PGC-1 alpha 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-1 alpha with concomitant suppression of fatty acid oxidation/mitochondrial genes. Transverse aortic constriction in mice decreased the basal expression of PGC-1 alpha and its downstream genes. Reduction of OGlcNAc signaling alleviated suppression of PGC-1 alpha 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-1 alpha upregulation even in the absence of hypertrophy. Finally, we found that PGC-1 alpha itself is O-GlcNAcylated. Together, these results reveal the recruitment of O-GlcNAc signaling as a potentially novel regulator of PGC-1 alpha activity during cardiac hypertrophy. Furthermore, O-GlcNAc signaling may mediate constitutive suppression of PGC-1 alpha 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.