The Role of HDAC9/MITR in the Pathogenesis of Thoracic Aortic Aneurysm (TAA)

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 DESCRIPTION (provided by applicant): 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-β) signaling pathway, or alternatively encode positive effectors of smooth muscle contractile function. These human diseases have been termed transforming growth factor-β vasculopathies (TGFβVs) or smooth muscle contraction vasculopathies (SMCVs), respectively. Despite the aortic phenotypic similarities between TGFβVs and SMCVs, mechanistic links between the two forms of TAA remain obscure. To identify pathogenetic similarities between TGFβVs 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 TGFβVs 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 (TGFβV) 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).