An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm

Christian L Lino Cardenas,Ashish S Yeri,Brian Ghoshhajra,Eric M Isselbacher,Patrick Ellinor,Saifar Nuri,Carolyn Macdonald,Mark E Lindsay,Farouc A Jaffer,Naftali Kaminski,Thomas Macgillivray,Chase W Kessinger,Neal L Weintraub,Luai Huleihel,Rajeev Malhotra,Yisha Cheng

doi:10.1038/s41467-018-03394-7

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.

Highlights

Thoracic aortic aneurysm (TAA) has been associated with mutations affecting members of the transforming growth factor-β (TGF-β) signaling pathway, or components and regulators of the vascular smooth muscle cell (VSMC) actomyosin cytoskeleton
We show that HDAC9, in cooperation with brahma-related gene 1 protein (BRG1) and MALAT1, mediates a critical epigenetic pathway responsible for VSMC dysfunction
The genes SMAD3 and TGFB2 (TGFβVs) as well as ACTA2 and MYH11 (SMVCs) fulfilled this criterion and were selected for specific siRNA targeting after proven bioactivity (Fig. 1a and Supplementary Fig. 1a)

Summary

Introduction

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 Both clinical groups present similar phenotypes, the existence of potential common mechanisms of pathogenesis remain obscure. We show that HDAC9, in cooperation with BRG1 and MALAT1, mediates a critical epigenetic pathway responsible for VSMC dysfunction These data offer the first mechanistic link between the two major categories of human genetically triggered aortic aneurysm (TGFβVs and SMCVs), and have therapeutic implications for treatment of aortic aneurysm, and other HDAC9-associated human vascular diseases involving VSMC function, including hypertension[17], intracranial aneurysms[18], ischemic stroke[19], and myocardial infarction[20]

Methods

Results

Conclusion