Final Report Summary - ENIGMA (Enigma – Histone Deacetylase protein complex controls cardiac hypertrophy)
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. 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. In the cytoplasm HDAC4 binds to the LIM domains of the adaptor protein ENIGMA (Pdlim7) to promote vascular ossification of VSMCs. We identified a new role and a new mechanistic paradigm for HDAC4.We provide multiple lines of evidence that the cytoplasmic activity of HDAC4 promotes vascular calcification, and identify HDAC4, and ENIGMA as mediators of this pathological process.