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Aneurysm Formation in Patients with Bicuspid Aortic Valves: Potential Role of Epigenetic Regulation of Gene Expression
Michael A. Hagler1, Aiham H. Jbeli1, Meghana Kunkala1, Carolyn M. Roos1, Thoralf M. Sundt2, Jordan D. Miller1.
1Mayo Clinic, Rochester, MN, USA, 2Massachusetts General Hospital, Boston, MA, USA.

Objective: Bicuspid aortic valve (BAV) disease occurs in 1-2% of the population, and is associated with a high prevalence of thoracic aortic aneurysm (TAA). Previous work has implicated loss-of-function mutations in Notch1 as a potential contributor to aneurysm formation in BAV patients with TAA, which may exert its effects through increased fibrosis and matrix remodeling. DNA promoter hypermethylation has been shown to repress Notch1 signaling in skeletal muscle, but epigenetic modifiers of gene expression have not been extensively characterized in patients with BAV and TAA. We thus tested the hypothesis that increases in DNA methyltransferases (DNMTs) downregulate Notch1 expression in TAA samples from patients with bicuspid aortic valves.
Methods: TAA samples were acquired from patients with BAV undergoing surgery (n=27) while normal aortic samples were acquired from non-aneurysmal hearts/aorta not suitable for cardiac transplant (n=13). We used qRT-PCR to measure mRNA levels of DNMT1, 3a, 3b and Notch1 in normal and TAA samples, and Western blotting to confirm changes in protein levels of DNMT3b.
Results: Compared to non-aneurysmal tissue, we found significantly increased mRNA levels of DNMT3a (1.38± 0.06) and DNMT3b (1.83± 0.17) in BAV/TAA samples (p < 0.05 for both), whereas DNMT1 was unchanged. In addition we found DNMT3b (2.82± 0.29, p < 0.05) protein levels were elevated in TAA tissue (n=10) in compassion to normal aorta (n=10). Surprisingly and in contrast to our hypothesis, Notch1 was significantly increased in BAV/TAA tissue compared to control samples (1.68± 0.19).
Conclusions: In conclusion these data are first to demonstrate increased DNA methyltransferase levels in thoracic aortic aneurysm tissue from patients with BAV. Surprisingly, and in contrast to our working hypothesis, Notch1 gene expression was increased in BAV/TAA tissue. Collectively, our data suggest that DNMT3a/b target genes are likely to be highly context dependent and tissue specific, and that de novo DNA methylation may suppress activity of protective signaling pathways independent of Notch1.

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