טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentAbend Alon
SubjectMolecular Mechanisms of Extra-Skeletal Ossification -
Histone Deacetylases (HDACs) are Potent Inducers
of Calcification
DepartmentDepartment of Medicine
Supervisor Professor Izhak Kehat


Abstract

A pathologic osteochondrogenic differentiation of vascular smooth muscle cells (VSMCs) promotes arterial calcifications, a process associated with significant morbidity and mortality. The molecular pathways promoting this pathology are not completely understood. We studied VSMCs, mouse aortic rings and human aortic valves and found that Histone Deacetylase 4 (HDAC4) is upregulated early in the calcification process. Gain- and loss- of function approaches demonstrated that HDAC4 is a positive regulator driving this pathology. HDAC4 can shuttle between the nucleus and cytoplasm, but in VSMCs the cytoplasmic rather than the nuclear activity of HDAC4 promotes calcification, and a nuclear mutant of HDAC4 failed to promote calcification. The cytoplasmic location and function of HDAC4 is controlled by the activity of salt inducible kinase (SIK). Pharmacologic inhibition of SIK sends HDAC4 to the nucleus and inhibits the calcification process in VSMCs, aortic rings and in vivo. 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.