Open AccessHDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype
Author(s) -
Rajeev Malhotra,
Andreas C. Mauer,
Christian L. Lino Cárdenas,
Xiuqing Guo,
Jie Yao,
Xiaoling Zhang,
Florian Wunderer,
Albert V. Smith,
Quenna Wong,
Sonali Pechlivanis,
Shih Jen Hwang,
Judy Wang,
Lingyi Lu,
Christopher 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 Buys,
Catherine Y. Campbell,
Tamara B. Harris,
Matthew J. Budoff,
Michael H. Criqui,
Jerome I. Rotter,
Andrew D. Johnson,
Ci Song,
Nora Franceschini,
Stéphanie Debette,
Udo Hoffmann,
Hagen Kälsch,
Markus M. Nöthen,
Sigurður Sigurðsson,
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
Publication year - 2019
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/s41588-019-0514-8
Subject(s) - biology , phenotype , calcification , vascular smooth muscle , cell , medicine , smooth muscle , genetics , endocrinology , gene
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.