O-GlcNAcylation-induced GSK-3β activation deteriorates pressure overload-induced heart failure via lack of compensatory cardiac hypertrophy in mice

Abstract

O-GlcNAc transferase (OGT) modulates many functions of proteins via O-GlcNAcylation that adds O-linked β-N-acetylglucosamine (O-GlcNAc) to the serine/threonine residues of proteins. However, the role of O-GlcNAcylation in cardiac remodeling and function is not fully understood. To examine the effect of O-GlcNAcylation on pressure overload-induced cardiac hypertrophy and subsequent heart failure, transverse aortic constriction (TAC) surgery was performed in wild type (WT) and Ogt transgenic (Ogt-Tg) mice. Four weeks after TAC (TAC4W), the heart function of Ogt-Tg mice was significantly lower than that of WT mice (reduced fractional shortening and increased ANP levels). The myocardium of left ventricle (LV) in Ogt-Tg mice became much thinner than that in WT mice. Moreover, compared to the heart tissues of WT mice, O-GlcNAcylation of GSK-3β at Ser9 was increased and phosphorylation of GSK-3β at Ser9 was reduced in the heart tissues of Ogt-Tg mice, resulting in its activation and subsequent inactivation of nuclear factor of activated T cell (NFAT) activity. Finally, the thinned LV wall and reduced cardiac function induced by TAC4W in Ogt-Tg mice was reversed by the treatment of a GSK-3β inhibitor, TDZD-8. These results imply that augmented O-GlcNAcylation exacerbates pressure overload-induced heart failure due to a lack of compensatory cardiac hypertrophy via O-GlcNAcylation of GSK-3β, which deprives the phosphorylation site of GSK-3β to constantly inactivate NFAT activity to prevent cardiac hypertrophy. Our findings may provide a new therapeutic strategy for cardiac hypertrophy and subsequent heart failure.

Roles of O-GlcNAcylation in Mitochondrial Homeostasis and Cardiovascular Diseases

“…Glucosamine or glutamine treatment promotes the activity of O-GlcNAcylation by increasing HBP flow. Pharmacological inhibitors of OGA include PUGNAc [5,34,35], Thiamet G [36,37], NAG thiazoline [38] or NButG [8,39], as well as the genetic inhibition of O-GlcNAcase by siRNA, or overexpressing OGT expression through adenovirus could increase the formation of O-GlcNAc [26]. The pharmaceutical GFAT inhibition with the glutamine analogue azaserine, or GFAT inhibitor DON [40] and Azaserine [41], or OGT inhibition with TTO4, OSMI or UDP-5SGlcNAc [42][43][44] can block O-GlcNAcylation.…”

“…Mitochondrial protein O-GlcNAcylation plays an important role in regulating cellular function; the destruction of O-GlcNAcylation homeostasis is involved in the pathogenesis of chronic diseases such as diabetes [43,72,73], neurodegenerative diseases [74,75], tumors [28,76,77] and CVDs [14,26,44]. Insulin resistance and diabetic CVDs are promoted by O-GlcNAcylation through an increase in the imbalance of multiple signaling pathways at the transcriptional, translational and posttranslational levels.…”

“…The cardiovascular system is complex, and the posttranslational modification of serine and threonine residues in nuclear, cytoplasmic and mitochondrial proteins by O-GlcNAcylation is considered an important regulatory mechanism in the cardiovascular system. Changes in O-GlcNAcylation may lead to many metabolic imbalances and affect cardiovascular function; and this process has an prominent role in heart remodeling [55,120,121], heart failure [22,26,122], diabetic cardiomyopathy [123][124][125], ischemic heart disease [24,42,126], hypertension [127] and arrhythmia [128,129]. Protein O-GlcNAcylation reprograms the cardiac substrate metabolism under chronic stress to advantageously alter adaptation [130].…”

“…Further research revealed that OGT transgenic mice exhibit a significant decrease in cardiac function and thinning of the left ventricle myocardium with cardiac systolic dysfunction four weeks after TAC surgery. Moreover, the O-GlcNACylation of GSK-3β at Ser9 was increased, and the O-GlcNAcylation of GSK-3β caused compensatory cardiac hypertrophy to mediate increased O-GlcNAcylation-aggravated pressure-overload-induced heart failure [26]. The PGC-1α as a key factor in regulating metabolism is crucial for normal cardiac function.…”

“…Elevated O-GlcNAcylation in the cardiovascular system is considered as a potential self-protection warning signal or pressure response [22,23]. And enhancing O-GlcNAcylation can increase the survival rate of cells under acute stress conditions, including hypoxia, local ischemia, oxidative stress and so on [22,24,25]; both decreased and increased O-GlcNAc levels can promote heart failure [26]. All these findings indicate that the imbalance of O-GlcNAcylation is closely related to CVDs.…”