HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype

Nat Genet. 2019 Nov;51(11):1580-1587. doi: 10.1038/s41588-019-0514-8. Epub 2019 Oct 28.

Abstract

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Animals
  • Aorta / metabolism
  • Aorta / pathology
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology*
  • Cohort Studies
  • Female
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Histone Deacetylases / physiology*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Muscle Contraction*
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology*
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Repressor Proteins / physiology*
  • Vascular Calcification / genetics
  • Vascular Calcification / metabolism
  • Vascular Calcification / pathology*

Substances

  • GTPase-Activating Proteins
  • RAP1GAP protein, human
  • Repressor Proteins
  • HDAC9 protein, human
  • Hdac9 protein, mouse
  • Histone Deacetylases