Most aging individuals have progressively enlarging accumulation of calcium in their major arteries. These vascular calcifications, that appear in the walls of blood vessels such as the aorta, coronary, carotid and femoral arteries and in the leaflets of heart valves cause stiffness and impair hemodynamics resulting in hypertension and organ ischemia, valve stenosis, cardiac hypertrophy, and congestive heart failure. The presence of such calcification in any arterial wall is associated with a 3–4-fold higher risk for mortality and cardiovascular events. We are trying to elucidate the molecular mechanisms responsible for vascular and valve calcifications and find novel approaches to stop this devastating process.
We showed that HDAC4 is a positive regulator driving this pathology. HDAC4 can shuttle between the nucleus and cytoplasm, but the cytoplasmic rather than the nuclear activity of HDAC4 promotes calcification. The cytoplasmic location and function of HDAC4 is controlled by the activity of salt-inducible kinase (SIK). In the cytoplasm, HDAC4 binds and its activity depends on the adaptor protein ENIGMA (Pdlim7) to promote vascular calcification. These results establish a cytoplasmic role for HDAC4 and identify HDAC4, SIK, and ENIGMA as mediators of vascular calcification.
Paper by Alon Abend (MD/PhD candidate):
Abend A, Shkedi O, Fertouk M, Caspi LH, Kehat I. Salt-inducible kinase induces cytoplasmic histone deacetylase 4 to promote vascular calcification. EMBO Rep. 2017 Jul;18(7):1166-1185