Clinical Science (2016) 130, 1389–1405 doi: 10.1042/CS20160222 Epigenetic regulation of TGF-β 1 signalling in dilative aortopathy of the thoracic ascending aorta Amalia Forte*, Umberto Galderisi*, Marilena Cipollaro*, Marisa De Feo† and Alessandro Della Corte† *Experimental Medicine, Second University of Naples, Naples, Italy †Cardiothoracic Sciences, Second University of Naples, Naples, Italy Abstract The term ‘epigenetics’ refers to heritable, reversible DNA or histone modifications that affect gene expression without modifying the DNA sequence. Epigenetic modulation of gene expression also includes the RNA interference mechanism. Epigenetic regulation of gene expression is fundamental during development and throughout life, also playing a central role in disease progression. The transforming growth factor β 1 (TGF-β 1 ) and its downstream effectors are key players in tissue repair and fibrosis, extracellular matrix remodelling, inflammation, cell proliferation and migration. TGF-β 1 can also induce cell switch in epithelial-to-mesenchymal transition, leading to myofibroblast transdifferentiation. Cellular pathways triggered by TGF-β 1 in thoracic ascending aorta dilatation have relevant roles to play in remodelling of the vascular wall by virtue of their association with monogenic syndromes that implicate an aortic aneurysm, including Loeys–Dietz and Marfan’s syndromes. Several studies and reviews have focused on the progression of aneurysms in the abdominal aorta, but research efforts are now increasingly being focused on pathogenic mechanisms of thoracic ascending aorta dilatation. The present review summarizes the most recent findings concerning the epigenetic regulation of effectors of TGF-β 1 pathways, triggered by sporadic dilative aortopathy of the thoracic ascending aorta in the presence of a tricuspid or bicuspid aortic valve, a congenital malformation occurring in 0.5–2 % of the general population. A more in-depth comprehension of the epigenetic alterations associated with TGF-β 1 canonical and non-canonical pathways in dilatation of the ascending aorta could be helpful to clarify its pathogenesis, identify early potential biomarkers of disease, and, possibly, develop preventive and therapeutic strategies. Key words: aneurysm, bicuspid aortic valve, epigenetics, TGF-β 1 pathway, thoracic ascending aorta. DILATIVE AORTOPATHY OF THE ASCENDING AORTA The term ‘aortopathy’ defines a group of disorders character- ized by dilatation, aneurysms, dissection and tortuosity of the aorta. Aortopathies may be sporadic, syndromic or familial non- syndromic [1]. An aortic aneurysm is defined as a localized or diffuse dilatation of the aorta with a diameter at least 1.5-fold greater than the expected normal size [2]. Demographic studies have indicated an epidemiological het- erogeneity of thoracic and abdominal aortic aneurysms (AAAs), Abbreviations: α-SMA, α-smooth muscle actin; AAA, abdominal aortic aneurysm; BAV, bicuspid aortic valve; COL1A, collagen type 1α; CREB, cAMP response element-binding protein; CTGF, connective tissue growth factor; DNMT, DNA methyltransferases; EC, endothelial cell; ECM, extracellular matrix; EMT, epithelial-to-mesenchymal transition; ENG, endoglin; eNOS, endothelial nitric oxide synthase; FBN, fibrillin; FN, fibronectin; HAT, histone acetyltransferase; HDAC, histone deacetylase; HIF, hypoxia-inducible factor; KLF, Kruppel-like factor; LTBP , latent TGF-β 1 -binding protein; MF, myofibroblast; MMP , matrix metalloproteinase; NGS, next-generation sequencing; RL, right–left; RNAi, RNA interference; sENG, soluble endoglin; SMC, smooth muscle cell; SOD, superoxide dismutase; SRF, serum response factor; TAA, thoracic ascending aortic aneurysm; TAV, tricuspid aortic valve; TET, 10–11 enzyme; TGF-β 1 , transforming growth factor β 1 ; TGIF, 5 ′ -TG–3 ′ -interacting factor; TIMP , tissue inhibitor of metalloproteinase; TSA, trichostatin A. Correspondence: A. Forte (amalia.forte@unina2.it). with about 9 % of the population aged 65 years affected by AAAs [3], whereas the incidence of thoracic ascending aortic aneurysms (TAAs) is estimated to be 5.9/100000 per year, a rate markedly lower but increasing by virtue of advances in imaging methods and screening [4]. Different rates of aneurysm incidence in the abdominal and thoracic aorta are related mainly to marked heterogeneity at a molecular and structural level, which has been well reviewed elsewhere [5], e.g. it has been highlighted that matrix metallo- proteinase (MMP)-2 and MMP-9 play a role in both TAAs and AAAs, but are produced by different cell types and with different C  2016 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society. 1389 Downloaded from https://portlandpress.com/clinsci/article-pdf/130/16/1389/447677/cs1301389.pdf by guest on 12 June 2020