Cytoplasmic Histone Deacetylase 4 Promotes Vascular Calcification

Background: Arterial calcification and valvular calcifications are associated with significant morbidity and mortality. Studies have now conclusively showed that an osteochondrogenic differentiation of vascular smooth muscle cells (VSMC) is a key mechanism in the development of vascular calcification, opening a direction for therapeutic interventions. Objective: To identify the role, subcellular location and mechanism of action of class IIa Histone deacetylase 4 (HDAC4) in vascular calcification Methods and Results: We used VSMCs, ex-vivo mouse aortic rings and human calcified aortic valves to show that HDAC4 is upregulated in vascular and valve calcification. Despite being exclusively cytoplasmic in VSMCs we show using both gain- and loss- of function approaches that HDAC4 is a positive regulator of the process. The cytoplasmic location of HDAC4 is controlled by the activity of salt inducible kinase (SIK) and the inhibition of SIK sends HDAC4 to the nucleus and inhibits the ossification process. In the c...