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HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype
Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA;Harvard Med Sch, Boston, MA 02115 USA.ORCID iD: 0000-0003-0120-4630
Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA.
Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA;Harvard Med Sch, Boston, MA 02115 USA.
Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA.
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 11, p. 1580-+Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 51, no 11, p. 1580-+
National Category
Cardiac and Cardiovascular Systems
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URN: urn:nbn:se:uu:diva-397651DOI: 10.1038/s41588-019-0514-8ISI: 000494714300006PubMedID: 31659325OAI: oai:DiVA.org:uu-397651DiVA, id: diva2:1374866
Funder
Swedish Research Council, 2016-00598German Research Foundation (DFG), Wu 841/1-1; ER 155/6-1; ER 155/6-2; PE 2309/2-1; TRR259; 426128588; 390873048NIH (National Institute of Health), R01-HL-117078Available from: 2019-12-03 Created: 2019-12-03 Last updated: 2019-12-03Bibliographically approved

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