HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.
Nat Genet
; 51(11): 1580-1587, 2019 11.
Article
in En
| MEDLINE
| ID: mdl-31659325
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Repressor Proteins
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Genetic Predisposition to Disease
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Atherosclerosis
/
Vascular Calcification
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Histone Deacetylases
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Muscle Contraction
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Muscle, Smooth, Vascular
Type of study:
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
/
Systematic_reviews
Limits:
Aged
/
Animals
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Female
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Humans
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Male
/
Middle aged
Language:
En
Journal:
Nat Genet
Journal subject:
GENETICA MEDICA
Year:
2019
Document type:
Article
Affiliation country:
Estados Unidos