Aortic aneurysm is common, affecting up to 1% of people in the United States. Risk factors for aortic aneurysm include hypertension, hypercholesterolemia, and male sex. In contrast to aneurysm of the abdominal aorta, aneurysmal dilation of the ascending thoracic aorta (TAA) is heavily influenced by genetic predisposition, often associated with a Mendelian inheritance pattern. Considerable progress has been made in the elucidation of aneurysm pathogenesis through the clinical and experimental study of Mendelian disorders closely associated with TAA, such as Marfan syndrome (MFS) or Loeys-Dietz syndrome (LDS). Genes involved in TAA often encode members of the canonical transforming growth factor beta (TGF-?) signaling pathway, or alternatively encode positive effectors of smooth muscle contractile function. These human diseases have been termed transforming growth factor-? vasculopathies (TGF?Vs) or smooth muscle contraction vasculopathies (SMCVs), respectively. Despite the aortic phenotypic similarities between TGF?Vs and SMCVs, mechanistic links between the two forms of TAA remain obscure. To identify pathogenetic similarities between TGF?Vs and SMCVs we created human vascular smooth muscle cellular models of genetically-triggered TAA and examined transcriptional signatures through microarray profiling. Transcripts were sought that showed similar dysregulation across these two groups. Interestingly, the epigenetic effector HDAC9 was found to be upregulated in TGF?Vs and SMCVs. Interestingly, HDAC9 has recently been implicated in genome wide association screens (GWAS) involving patients with both large vessel stroke as well as coronary artery disease, although its mechanism of action in these human vascular diseases is poorly understood. In our experiments, cells expressing aneurysm transgenes mimicking human mutations TGFBR2G357W (TGF?V) and ACTA2R179H (SMCV) were found to have reduced migratory capacity, cytoskeletal abnormalities, and reduced expression of VSMC-specific transcripts for smoothelin, calponin, and vinculin. Importantly all of these phenotypes could be suppressed by siRNA mediated silencing of HDAC9. We went on to document increased expression of HDAC9 in aortas of Marfan (Fbn1C1039G/+) and Loeys-Dietz type 4 mice (Tgfb2-/+) that was accompanied by decreased VSMC specific protein expression, recapitulating in vitro observations. These preliminary data implicate HDAC9 as a critical mediator of vascular pathogenesis in TAA. In this application we will extensively investigate the mechanism of HDAC9 transcriptional induction (AIM1), the effect of increased HDAC9 on vascular smooth muscle cell phenotype (AIM2), and the feasibility of targeting HDAC9 activity for therapeutic benefit in experimental aortic aneurysm (AIM3).

Public Health Relevance

In this study we are looking to understand common features driving diverse types of human aortic aneurysm. Aortic aneurysms have a risk of tear, called 'dissection', associated with a very high risk of death. Using molecular techniques we have identified involvement of a DNA-binding protein named HDAC9 responsible for controlling the attributes of vascular smooth muscle cells, the primary cell type within the aorta. We will extensively study the ways in which this protein controls DNA within vascular smooth muscle cells to cause dysfunction of the aorta and look for ways to inhibit the protein in order to preven progression of aortic disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL130113-04
Application #
9619290
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Tolunay, Eser
Project Start
2016-01-15
Project End
2020-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
Isselbacher, Eric M; Lino Cardenas, Christian Lacks; Lindsay, Mark E (2016) Hereditary Influence in Thoracic Aortic Aneurysm and Dissection. Circulation 133:2516-28