Abstract

Thoracic aortic aneurysm (TAA) has been associated with mutations affecting members of the TGF-β signaling pathway, or components and regulators of the vascular smooth muscle cell (VSMC) actomyosin cytoskeleton. Although both clinical groups present similar phenotypes, the existence of potential common mechanisms of pathogenesis remain obscure. Here we show that mutations affecting TGF-β signaling and VSMC cytoskeleton both lead to the formation of a ternary complex comprising the histone deacetylase HDAC9, the chromatin-remodeling enzyme BRG1, and the long noncoding RNA MALAT1. The HDAC9–MALAT1–BRG1 complex binds chromatin and represses contractile protein gene expression in association with gain of histone H3-lysine 27 trimethylation modifications. Disruption of Malat1 or Hdac9 restores contractile protein expression, improves aortic mural architecture, and inhibits experimental aneurysm growth. Thus, we highlight a shared epigenetic pathway responsible for VSMC dysfunction in both forms of TAA, with potential therapeutic implication for other known HDAC9-associated vascular diseases.

Details

Title
An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm
Author
Lino Cardenas, Christian L 1   VIAFID ORCID Logo  ; Kessinger, Chase W 2 ; Cheng, Yisha 1 ; MacDonald, Carolyn 1 ; MacGillivray, Thomas 3 ; Ghoshhajra, Brian 4 ; Huleihel, Luai 5 ; Saifar Nuri 1 ; Yeri, Ashish S 6 ; Jaffer, Farouc A 2   VIAFID ORCID Logo  ; Kaminski, Naftali 7   VIAFID ORCID Logo  ; Ellinor, Patrick 8   VIAFID ORCID Logo  ; Weintraub, Neal L 9 ; Malhotra, Rajeev 2 ; Isselbacher, Eric M 1 ; Lindsay, Mark E 10 

1  Thoracic Aortic Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 
2  Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 
3  Thoracic Aortic Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 
4  Thoracic Aortic Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 
5  McGowan Institute for Regenerative Medicine and Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Pulmonary, Critical Care, and Sleep Medicine, Yale University, New Haven, CT, USA 
6  Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 
7  Pulmonary, Critical Care, and Sleep Medicine, Yale University, New Haven, CT, USA 
8  Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Cardiovascular Genetics Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 
9  Augusta University/Medical College of Georgia, Augusta, GA, USA 
10  Thoracic Aortic Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Cardiovascular Genetics Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Pediatric Cardiology, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 
Pages
1-14
Publication year
2018
Publication date
Mar 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-03394-7
ProQuest document ID
2012135805
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.