HDAC4-knockout mice develop heart failure in models of type 1 and type 2 diabetes mellitus, whereas wild-type mice do not develop clear signs of heart failure, indicating that HDAC4 protects the diabetic heart.
We conclude that HDAC4 plays a central role for rapid modifications of histone methylation in response to variations in cardiac load and may represent a target for pharmacological interventions to prevent maladaptive remodeling in patients with heart failure.
These findings identify HDAC4 as a specific downstream substrate of CaMKIIdeltaB in cardiac cells and have broad applications for the signaling pathways leading to cardiac hypertrophy and heart failure.