Premium
Salt‐inducible kinase induces cytoplasmic histone deacetylase 4 to promote vascular calcification
Author(s) -
Abend Alon,
Shkedi Omer,
Fertouk Michal,
Caspi Lilac H,
Kehat Izhak
Publication year - 2017
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201643686
Subject(s) - histone deacetylase , calcification , cytoplasm , vascular smooth muscle , microbiology and biotechnology , histone deacetylase 5 , hdac10 , hdac4 , downregulation and upregulation , hdac11 , chemistry , biology , histone , cancer research , biochemistry , endocrinology , medicine , smooth muscle , gene
A pathologic osteochondrogenic differentiation of vascular smooth muscle cells ( VSMC s) promotes arterial calcifications, a process associated with significant morbidity and mortality. The molecular pathways promoting this pathology are not completely understood. We studied VSMC s, mouse aortic rings, and human aortic valves and showed here that histone deacetylase 4 ( HDAC 4) is upregulated early in the calcification process. Gain‐ and loss‐of‐function assays demonstrate that HDAC 4 is a positive regulator driving this pathology. HDAC 4 can shuttle between the nucleus and cytoplasm, but in VSMC s, the cytoplasmic rather than the nuclear activity of HDAC 4 promotes calcification, and a nuclear‐localized mutant of HDAC 4 fails to promote calcification. The cytoplasmic location and function of HDAC 4 is controlled by the activity of salt‐inducible kinase ( SIK ). Pharmacologic inhibition of SIK sends HDAC 4 to the nucleus and inhibits the calcification process in VSMC s, aortic rings, and in vivo . In the cytoplasm, HDAC 4 binds and its activity depends on the adaptor protein ENIGMA (Pdlim7) to promote vascular calcification. These results establish a cytoplasmic role for HDAC 4 and identify HDAC 4, SIK , and ENIGMA as mediators of vascular calcification.