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

Malhotra, Rajeev ; Mauer, Andreas C ; Lino Cardenas, Christian L ; Guo, Xiuqing ; Yao, Jie ; Zhang, Xiaoling ; Wunderer, Florian ; Smith, Albert V ; Wong, Quenna ; Pechlivanis, Sonali ; Hwang, Shih-Jen ; Wang, Judy ; Lu, Lingyi ; Nicholson, Christopher J ; Shelton, Georgia ; Buswell, Mary D ; Barnes, Hanna J ; Sigurslid, Haakon H ; Slocum, Charles ; Rourke, Caitlin O' ; Rhee, David K ; Bagchi, Aranya ; Nigwekar, Sagar U ; Buys, Emmanuel S ; Campbell, Catherine Y ; Harris, Tamara ; Budoff, Matthew ; Criqui, Michael H ; Rotter, Jerome I ; Johnson, Andrew D ; Song, Ci ; Franceschini, Nora ; Debette, Stephanie ; Hoffmann, Udo ; Kälsch, Hagen ; Nöthen, Markus M ; Sigurdsson, Sigurdur ; Freedman, Barry I ; Bowden, Donald W ; Jöckel, Karl-Heinz ; Moebus, Susanne ; Erbel, Raimund ; Feitosa, Mary F ; Gudnason, Vilmundur ; Thanassoulis, George ; Zapol, Warren M ; Lindsay, Mark E ; Bloch, Donald B ; Post, Wendy S ; O'Donnell, Christopher J

Nature genetics, 2019-11, Vol.51 (11), p.1580-1587 [Periódico revisado por pares]

United States: Nature Publishing Group

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Título:
HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype
Autor: Malhotra, Rajeev ; Mauer, Andreas C ; Lino Cardenas, Christian L ; Guo, Xiuqing ; Yao, Jie ; Zhang, Xiaoling ; Wunderer, Florian ; Smith, Albert V ; Wong, Quenna ; Pechlivanis, Sonali ; Hwang, Shih-Jen ; Wang, Judy ; Lu, Lingyi ; Nicholson, Christopher J ; Shelton, Georgia ; Buswell, Mary D ; Barnes, Hanna J ; Sigurslid, Haakon H ; Slocum, Charles ; Rourke, Caitlin O' ; Rhee, David K ; Bagchi, Aranya ; Nigwekar, Sagar U ; Buys, Emmanuel S ; Campbell, Catherine Y ; Harris, Tamara ; Budoff, Matthew ; Criqui, Michael H ; Rotter, Jerome I ; Johnson, Andrew D ; Song, Ci ; Franceschini, Nora ; Debette, Stephanie ; Hoffmann, Udo ; Kälsch, Hagen ; Nöthen, Markus M ; Sigurdsson, Sigurdur ; Freedman, Barry I ; Bowden, Donald W ; Jöckel, Karl-Heinz ; Moebus, Susanne ; Erbel, Raimund ; Feitosa, Mary F ; Gudnason, Vilmundur ; Thanassoulis, George ; Zapol, Warren M ; Lindsay, Mark E ; Bloch, Donald B ; Post, Wendy S ; O'Donnell, Christopher J
Assuntos: Abdomen ; African Americans ; Aged ; Animals ; Aorta ; Aorta - metabolism ; Aorta - pathology ; Arteriosclerosis ; Atherosclerosis ; Atherosclerosis - genetics ; Atherosclerosis - metabolism ; Atherosclerosis - pathology ; Calcification ; Calcification (ectopic) ; Cardiovascular diseases ; Cohort Studies ; Coronary vessels ; Evaluation ; Female ; Gene expression ; Gene loci ; Genetic aspects ; Genetic Predisposition to Disease ; Genome-wide association studies ; Genome-Wide Association Study ; Genomes ; GTPase-Activating Proteins - genetics ; GTPase-Activating Proteins - metabolism ; Health aspects ; Heart ; Hispanic Americans ; Histone Deacetylases - genetics ; Histone Deacetylases - metabolism ; Histone Deacetylases - physiology ; Humans ; Life Sciences ; Male ; Meta-analysis ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Middle Aged ; Muscle Contraction ; Muscle, Smooth, Vascular - metabolism ; Muscle, Smooth, Vascular - pathology ; Muscles ; Phenotype ; Phenotypes ; Polymorphism, Single Nucleotide ; Proteins ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; Repressor Proteins - physiology ; Risk factors ; Santé publique et épidémiologie ; Signal transduction ; Single nucleotide polymorphisms ; Single-nucleotide polymorphism ; Smooth muscle ; Thorax ; Vascular Calcification - genetics ; Vascular Calcification - metabolism ; Vascular Calcification - pathology
É parte de: Nature genetics, 2019-11, Vol.51 (11), p.1580-1587
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Approval of content of manuscript: all authors
Concept and design of cell-based assays and in vivo studies: R.M.
Concept and design of genome-wide association study: R.M., A.C.M., X.G., J.Y., C.Y.C., W.S.P., C.J.O.
Critical revision of the manuscript for important intellectual content: all authors
Cohort-based phenotype and genotype acquisition: A.V.S., Q.W., S.P., S.-J.H., J.W., L.L., C.Y.C., T.H., M.B., M.H.C., J.I.R., A.D.J., C. Song, N.F., S.D., U.H., H.K., M.M.N., S.S., B.I.F., D.W.B., K.-H.J., S.M., R.E., M.F.F., V.G., G.T., W.S.P., C.J.O.
Meta-analysis and sQTL analysis: R.M., A.C.M., X.G., J.Y., X.Z., W.S.P., C.J.O.
Author Contributions
Drafting of the manuscript: R.M., A.C.M., C.J.O.
Acquisition, analysis, or interpretation of data in cell-based assays and in vivo studies: R.M., C.L.L.C., F.W., C.J.N., G.S., M.D.B., H.J.B., C. Slocum, H.H.S., C.O., D.K.R., A.B., S.U.N., E.S.B., W.M.Z., M.E.L., D.B.B.
Descrição: 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 ). 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.
Editor: United States: Nature Publishing Group
Idioma: Inglês

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

United States: Nature Publishing Group

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