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

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.

• Authors: Rajeev Malhotra, Andreas C Mauer, Christian L Lino Cardenas, Xiuqing Guo, Jie Yao, Xiaoling Zhang, Florian Wunderer, Albert V Smith, Quenna Wong, Sonali Pechlivanis, Shih-Jen Hwang, Judy Wang, Lingyi Lu, Christopher J Nicholson, Georgia Shelton, Mary D Buswell, Hanna J Barnes, Haakon H Sigurslid, Charles Slocum, Caitlin O' Rourke, David K Rhee, Aranya Bagchi, Sagar U Nigwekar, Emmanuel S Buys, Catherine Y Campbell, Tamara Harris, Matthew Budoff, Michael H Criqui, Jerome I Rotter, Andrew D Johnson, Ci Song, Nora Franceschini, Stephanie Debette, Udo Hoffmann, Hagen Kälsch, Markus M Nöthen, Sigurdur Sigurdsson, Barry I Freedman, Donald W Bowden, Karl-Heinz Jöckel, Susanne Moebus, Raimund Erbel, Mary F Feitosa, Vilmundur Gudnason, George Thanassoulis, Warren M Zapol, Mark E Lindsay, Donald B Bloch, Wendy S Post, Christopher J O'Donnell
• Journal: Nature genetics (Nat Genet) Vol. 51 Issue 11 Pg. 1580-1587 (11 2019) ISSN: 1546-1718 [Electronic] United States
• PMID: 31659325 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

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

Topics

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