Cardiac hypertrophy is a compensatory mechanism that allows the heart to maintain cardiac output under pressure overload. However, sustained pressure overload such as caused by hypertension or aortic stenosis eventually leads to maladaptive cardiac remodelling and ultimately to heart failure. Our lab has previously shown that activation of the AMP-activated protein kinase (AMPK) prevents cardiac hypertrophy by decreasing O-GlcNAcylation, a post-translational modification of proteins that is increased during cardiac hypertrophy and heart failure. The AMPK-mediated inhibition of protein O-GlcNAcylation is due to the direct phosphorylation and inhibition of the Glutamine:fructose-6-phosphate amidotransferase (GFAT), the rate limiting step of the hexosamine biosynthesis pathway, the glucose-related metabolic pathway responsible for the formation of the O-GlcNAc moiety. By using different types of AMPK activators and genetic model of AMPK-deficient mice, we investigated the capacity of chronic AMPK activation to reverse cardiac hypertrophy development when already installed and to prevent heart failure evolution. In a mechanistic point of view, we established an unbiased mass spectrometry-based proteomic approach to isolate and identify the O-GlcNacylated proteins from tissues or isolated cells. Such O-GlcNacylomic study allowed us to identify more than 1700 O-GlcNAcylated proteins in the failing heart. Analysis of this dataset has enabled us to identify several candidates responsible for the development of heart failure, with the aim of finding future innovative therapeutic approaches.

Luc Bertrand is invited by Benoit Viollet.