O-GlcNAcylation of Histone Deacetylase 4 Protects the Diabetic Heart from Failure.

BACKGROUND: World-wide, diabetes and heart failure represent frequent comorbidities with high socioeconomic impact and steadily growing incidence, calling for a better understanding of how diabetic metabolism promotes cardiac dysfunction. Paradoxically, some glucose-lowering drugs have been shown to worsen heart failure, raising the question of how glucose mediates protective versus detrimental cardiac signaling. Here, we identified a histone deacetylase 4 (HDAC4) subdomain as a molecular checkpoint of adaptive and maladaptive signaling in the diabetic heart.

METHODS: A conditional HDAC4 allele was used to delete HDAC4 specifically in cardiomyocytes (HDAC4-KO). Mice were subjected to diabetes either by streptozotocin injections (STZ; type 1 diabetes model) or by crossing into mice carrying a leptin receptor mutation (db/db; type 2 diabetes model) and monitored for remodeling and cardiac function. Effects of glucose and the posttranslational modification (PTM) by β-linked N-acetylglucosamine (O-GlcNAc) on HDAC4 were investigated in vivo and in vitro by biochemical and cellular assays.

RESULTS: We show that the cardio-protective N-terminal proteolytic fragment of HDAC4 (HDAC4-NT) is enhanced in vivo in diabetic patients and mouse models, as well as in vitro under high-glucose and high-O-GlcNAc conditions. HDAC4-KO mice develop heart failure in models of type 1 and type 2 diabetes whereas wild-type mice do not develop clear signs of heart failure, indicating that HDAC4 protects the diabetic heart. Re-expression of HDAC4-NT prevents HDAC4-dependent diabetic cardiomyopathy. Mechanistically, the PTM of HDAC4 at Ser-642 by O-GlcNAcylation is an essential step for HDAC4-NT production, which was attenuated by CaMKII-mediated phosphorylation at Ser-632. Preventing O-GlcNAcylation at Ser-642 did not only entirely preclude HDAC4-NT production but also promoted CaMKII-mediated phosphorylation at Ser-632, pointing to a mutual PTM crosstalk of (cardio-detrimental) phosphorylation at Ser-632 and (cardio-protective) O-GlcNAcylation at Ser-642.

CONCLUSIONS: In this study, we found that O-GlcNAcylation of HDAC4 at Ser-642 is cardio-protective in diabetes and counteracts pathological CaMKII signaling. We introduce a molecular model explaining how diabetic metabolism possesses important cardio-protective features besides its known detrimental effects. A deeper understanding of the here-described PTM crosstalk may lay the ground for the development of specific therapeutic concepts to treat heart failure in the context of diabetes.