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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?-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.

SUBMITTER: Malhotra R

PROVIDER: S-EPMC6858575 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Malhotra Rajeev R Mauer Andreas C AC Lino Cardenas Christian L CL Guo Xiuqing X Yao Jie J Zhang Xiaoling X Wunderer Florian F Smith Albert V AV Wong Quenna Q Pechlivanis Sonali S Hwang Shih-Jen SJ Wang Judy J Lu Lingyi L Nicholson Christopher J CJ Shelton Georgia G Buswell Mary D MD Barnes Hanna J HJ Sigurslid Haakon H HH Slocum Charles C Rourke Caitlin O' CO Rhee David K DK Bagchi Aranya A Nigwekar Sagar U SU Buys Emmanuel S ES Campbell Catherine Y CY Harris Tamara T Budoff Matthew M Criqui Michael H MH Rotter Jerome I JI Johnson Andrew D AD Song Ci C Franceschini Nora N Debette Stephanie S Hoffmann Udo U Kälsch Hagen H Nöthen Markus M MM Sigurdsson Sigurdur S Freedman Barry I BI Bowden Donald W DW Jöckel Karl-Heinz KH Moebus Susanne S Erbel Raimund R Feitosa Mary F MF Gudnason Vilmundur V Thanassoulis George G Zapol Warren M WM Lindsay Mark E ME Bloch Donald B DB Post Wendy S WS O'Donnell Christopher J CJ

Nature genetics 20191028 11

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<sup>-8</sup>). No SNPs were associated with thoracic aortic calcification at the ...[more]

PMID: 31659325

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Project description:BACKGROUND:Phenotypic transformation of vascular smooth muscle cells is a key element in vascular remodeling and aortic aneurysm growth. Previously, deletion of several inflammasome components decreased formation of aortic aneurysm (AA) in the Angiotensin II (AngII) -induced mouse model. We hypothesized that the inflammasome sensor Absent in melanoma 2 (Aim2) might affect the phenotype of vascular smooth muscle cells (VSMC), thereby reducing AA formation. METHODS:Aim2-/- mice and wild-type (WT) C57Bl/6?J mice were used as an animal model. VSMC were isolated from 6?months old mice and grown in vitro. Young (passage 3-5) and senescent (passage 7-12) cells were analyzed in vitro for calcification in mineralization medium by Alizarin Red S staining. Expression of calcification and inflammatory markers were studied by real-time RT-PCR and Western blotting, release of cytokines was determined by ELISA. To induce AA, osmotic mini-pumps loaded with AngII (1500?ng/kg bodyweight/min) were implanted for 28?days in male mice at 6?months of age. RESULTS:Compared with VSMC from WT mice, VSMC isolated from Aim2-/- mice were larger, less viable, and underwent stronger calcification in mineralization medium, along with induction of Bmp4 and repression of Tnfsf11/Rankl gene expression. In addition, Aim2 deficiency was associated with reduced inflammasome gene expression and release of Interleukin-6. Using the mouse model of AngII induced AA, Aim2 deficiency reduced AA incidence to 48.4% (15/31) in Aim2-/- mice versus 76.5% (13/17) in WT mice. In contrast to Aim2-/- mice, AA from WT mice expressed significantly increased levels of alpha-smooth muscle actin/Acta2, indicating tissue remodeling. Reduced cell proliferation in Aim2-/- mice was indicated by significantly increased p16ink4a/Cdkn2a expression in untreated and AngII-infused aortas, and by significantly lower amounts of proliferating (Ki67 positive) VSMC in AngII-infused Aim2-/- mice. CONCLUSIONS:Our results suggest a role for Aim2 in regulating VSMC proliferation and transition to an osteoblast-like or osteoclast-like phenotype, thereby modulating the response of VSMC in aortic remodeling and AA formation.

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

Publications

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

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