HDAC9 Is a Potential Therapeutic Target for Atherosclerotic Cardiovascular Disease
Key findings
- This genome-wide association study with more than 9,400 participants identified an association between abdominal aortic calcification (AAC) and six single-nucleotide polymorphisms (SNPs) in the HDAC9 locus
- Reducing the expression of HDAC9 prevented calcification of human aortic smooth muscle cells in vitro
- In a mouse model of human vascular calcification, HDAC9 knockout mice showed significantly reduced aortic calcification and significantly improved survival
- HDAC9 is a novel potential target for treatment of diseases related to vascular calcification
Aortic calcification is an important independent predictor of coronary events, stroke and cardiovascular death. However, no genetic determinant has been identified for either abdominal aortic calcification (AAC) or thoracic aortic calcification (TAC).
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Based on a meta-analysis of genome-wide association studies (GWAS), Rajeev Malhotra, MD, MS, cardiologist in the Cardiovascular Research Center, Donald B. Bloch, MD, physician in the Division of Rheumatology, Allergy and Immunology, Christopher J. O'Donnell, MD, researcher in the Center for Genomic Medicine at Massachusetts General Hospital, Wendy Post, MD, of Johns Hopkins, and an international team have pinpointed histone deacetylase 9 (HDAC9) as being associated with AAC—and capable of causing AAC by changing the phenotype of vascular smooth muscle cells. The team's report is published in Nature Genetics.
Discovery Stage: GWAS Meta-Analysis
Using data from the Cohorts for Heart and Aging Research in Genome Epidemiology Consortium (CHARGE), as published in Circulation, the researchers analyzed five cohorts of individuals of European ancestry:
- Framingham Heart Study (FHS)
- Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-RS)
- Multi-Ethnic Study of Atherosclerosis (MESA)
- Family Heart Study (FamHS)
- Heinz Nixdorf Recall study (HNR)
Imaging data quantifying the degree of vascular calcification was available for the abdominal aorta in 9,417 participants and for the descending thoracic aorta in 8,422 participants.
Six single-nucleotide polymorphisms (SNPs) associated with AAC were identified in a genetic locus encoding HDAC9, and two were identified in a locus encoding RAP1 GTPase activating protein 1 (RAP1GAP). The magnitudes of these associations were consistent across all five cohorts.
No SNPs were significantly associated with TAC at a genome-wide level of significance.
Validation Stage: GWAS Meta-analysis
The researchers then analyzed data on African Americans and Latinos using three additional cohorts:
- MESA (African American, n=343; Latino, n=496)
- FamHS (African American, n=621)
- African American-Diabetes Heart Study (AA-DHS, n=750)
In the Latino population in MESA, all six SNPs in the HDAC9 locus were significantly associated with AAC. Among African Americans, there were no such associations, except that in the FamHS cohort there was a modest association between AAC and one of the SNPs.
There were no associations between AAC and SNPs in the RAP1GAP locus in Latinos or African Americans.
Association of the SNPs with Cardiovascular Disease
The six polymorphisms in the HDAC9 locus were also found to be associated with myocardial infarction, coronary artery calcification and the presence of carotid artery plaque based on data collected in prior studies.
Functional Studies
Vascular calcification is characterized by the transition of vascular smooth muscle cells into osteoblast-like cells that deposit calcium phosphate in the extracellular space. Runt-related transcription factor 2 (RUNX2) is a master regulator of this change, which manifests as an increase in smooth muscle cell proliferation and reduced cell contractility.
In laboratory studies of human aortic smooth muscle cells that were treated with a calcifying medium, knockdown of HDAC9 expression inhibited RUNX2 expression, decreased cell proliferation and increased cell contractility.
In a complementary experiment, when the researchers increased expression of HDAC9 in the cells, they observed increased levels of RUNX2, increased calcification and reduced contractility.
Mouse Model of Vascular Calcification
In a mouse model of human vascular calcification, animals that lacked HDAC9 exhibited significantly reduced RUNX2 and aortic calcification, as well as significantly improved survival. Moreover, aortic smooth muscle cells isolated from the HDAC9 knockout mice were protected from calcification. These results imply that HDAC9 is an important contributor to the development of vascular calcification in vivo.
A Potential Unifying Mechanism
Several previous GWASs have detected an association between HDAC9 and large-vessel ischemic stroke, myocardial infarction and increased pulse pressure. Multiple other studies have linked these clinical events to aortic calcification.
By identifying HDAC9 as an activator of vascular calcification, the current study offers a potential unifying molecular mechanism for the associations of HDAC9 with stroke, myocardial infarction and pulse pressure. HDAC9 is a novel target for the treatment of atherosclerotic cardiovascular disease.
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