Targeting AMPK/O-GlcNAc axis to treat doxorubicin-induced cardiotoxicity

Details

Supervisors

Bertrand, Luc ; Russo, Michele

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

Anthracyclines, including doxorubicin (DOX) are highly effective chemotherapeutic drugs used to treat a wide spectrum of cancers. However, their administration is associated with the long-term onset of cardiotoxic events, leading to heart failure (HF). To date, the pathophysiology of DOX-induced cardiotoxicity (DIC) is still poorly understood. Recent studies have raised mitochondria as a main target of DOX in cardiomyocytes, leading to reactive oxygen species formation and dysregulation of Ca2+ and iron homeostasis. Collectively, these events result in mitochondrial dysfunction, which is associated with a metabolic reprogramming in cardiomyocytes, shifting from fatty acid 𝛽-oxidation to glucose utilisation. This metabolic switch contributes to the initiation and progression of HF in patients but the mechanistic link(s) between this metabolic rewiring and cardiac dysfunction is still largely unknown. Under physiological conditions, a small proportion of glucose enters in alternative metabolic pathways, including the hexosamine biosynthesis pathway (HBP). The final product of HBP is UDP-GlcNAc, the donor-substrate for protein O-GlcNAcylation (O-GlcNAc), a post- translational modification that plays a critical role in the regulation of cell metabolism and stress response. Previous work of my host laboratory showed that elevated O-GlcNAc levels are associated with the development of different types of cardiomyopathies, including cardiac hypertrophy and diabetic cardiomyopathy. However, its role in DIC is still undefined. My research project aimed to elucidate the involvement of protein O-GlcNAc during the initiation and progression of DIC. First, I evaluated the levels of O-GlcNAcylated proteins in isolated rat cardiomyocytes or mouse hearts treated with DOX, showing a significant increase in O- GlcNAcylated cardiac proteins in all DOX treated groups, related to changes in protein level of different enzymes involved in HBP/O-GlcNAc. Based on previous results of the host laboratory, showing the inhibitory effect of AMP-activated protein kinase (AMPK) on HBP and O-GlcNAc, the second objective of my project was to investigate the potential of various AMPK activators to counteract the DOX-induced increase in O-GlcNAc. Surprisingly, our findings indicate a partial preservation of O-GlcNAc levels in DOX-treated cardiomyocytes in combination with AMPK activators. All these observations allow us to speculate that O-GlcNAc could be a hitherto unidentified link between metabolic impairment and DIC but questioned the use of AMPK activators as therapeutic potential in the fight against DIC.