Salt-inducible kinase induces cytoplasmic histone deacetylase 4 to promote vascular calcification

EMBO Rep. 2017 Jul;18(7):1166-1185. doi: 10.15252/embr.201643686. Epub 2017 Jun 6.

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 showed here that histone deacetylase 4 (HDAC4) is upregulated early in the calcification process. Gain- and loss-of-function assays demonstrate 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-localized mutant of HDAC4 fails 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.

Keywords: histone deacetylase; smooth muscle cell; vascular calcification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Aortic Valve / physiopathology
  • Cell Differentiation
  • Cell Nucleus
  • Cytoplasm / chemistry
  • Cytoplasm / metabolism
  • Cytoskeletal Proteins / genetics
  • Gene Expression Regulation*
  • Histone Deacetylases / genetics*
  • Histone Deacetylases / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • LIM Domain Proteins / genetics
  • Mice
  • Muscle, Smooth, Vascular / pathology
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Up-Regulation
  • Vascular Calcification / genetics
  • Vascular Calcification / physiopathology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • Intracellular Signaling Peptides and Proteins
  • LIM Domain Proteins
  • PDLIM7 protein, human
  • Pdlim7 protein, mouse
  • Repressor Proteins
  • Protein-Tyrosine Kinases
  • Ptk6 protein, mouse
  • Protein-Serine-Threonine Kinases
  • SIK1 protein, human
  • HDAC4 protein, human
  • Hdac5 protein, mouse
  • Histone Deacetylases