Cardiac hypertrophy drives PGC-1α suppression associated with enhanced O-glycosylation

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1867

Article

Brainard, Robert E.^1,2  Facundo, Heberty T.^1,3 

[1] Univ Louisville, Dept Med, Inst Mol Cardiol, Louisville, KY 40292 USA

[2] Univ Louisville, Dept Physiol & Biophys, Louisville, KY 40292 USA

[3] Univ Fed Cariri, Fac Med, Barbalha, Ceara, Brazil

关键词: Cardiac hypertrophy;    O-GlcNAc;    Energy metabolism;    Gene regulation;    Heart failure - basic studies;   

DOI  :  10.1016/j.bbadis.2021.166080

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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