Transforming Growth Factor‐β in Thoracic Aortic Aneurysms: Good, Bad, or Irrelevant?

M arfan syndrome is a multisystem disorder, but its most devastating manifestations are aortic aneurysms and dissection. This syndrome results from mutations in FBN1, which encodes fibrillin-1, a microfibrillar protein that decorates the surface of elastin fibers. Over 100 known mutations in FBN1 cause Marfan syndrome, resulting in a wide variance of clinical presentations in affected individuals. While the genetic etiology of this disease is known, the mechanism explaining how these mutations promote a focal defect in the aorta has not been defined. One proposed hypothesis is through the intermediary role of a cytokine, transforming growth factor b (TGF-b). A publication in this issue of JAHA addresses the complex roles of TGF-b in development of experimental aortopathies. TGF-b is secreted in a latent form as a complex that includes the cytokine, a latency-associated peptide, and 1 of 3 members of the latent TGF-b binding protein (LTBP) family. This complex retains TGF-b in an inactive form by binding to extracellular matrix elements, including fibrillin-1. It has been proposed that fibrillin-1 mutants associated with Marfan syndrome reduce the binding of this complex to facilitate release of bioactive TGF-b. TGF-b has 3 isoforms that are sequentially numbered. While increased total TGF-b1 protein has been detected in tissue surgically removed from individuals with aortopathies, there was no detected increase of bioactive TGF-b1, as defined by the presence of the 25 kDa form. TGF-b2 and 3 were detected in minimal amounts. Although increased bioactive TGF-b has not been detected in Marfan syndrome–induced aortopathy, evidence for increased activity of this cytokine has been inferred from increased presence of mediators of intracellular signaling, primarily the phosphorylated form of SMAD2 (pSmad2). Indirect evidence supporting the role of excessive TGF-b in promoting aortopathies is that downregulation of LTBP3 attenuated disease and was associated with decreased abundance of pSmad2. More directly, a seminal publication demonstrated reduced dilation of the ascending aorta in fibrillin-1 haploinsufficient mice following administration of an antibody that neutralized activity of all TGF-b isoforms. Neutralization of TGF-b also reduced aortic size in hypercholesterolemic mice with CXCL10 deficiency during chronic angiotensin II infusion. Profound TGF-b neutralization using the mouse monoclonal antibody, 1D11, also improved survival in fibrillin-1 hypomorphic mice. While these early studies present a case for inhibition of TGF-b being a therapeutic strategy, evolving literature has painted a more confusing landscape for the role of TGF-b in aortopathies. This includes studies in which manipulation of TGF-b activity provided diametrically opposing data: increased TGF-b is protective against aortopathies. These studies have either administered TGF-b neutralizing antibodies or genetically manipulated TGF-b and its receptors to attenuate physiological function. Several studies have determined the effect of neutralizing TGF-b antibodies on experimental aortopathies with variable results. Some studies have demonstrated that administration of TGF-b antibodies had no effect on AngII-induced aortic dilation during profound neutralization. Conversely, profound TGF-b neutralization has been demonstrated to increase aortic rupture rates and aneurysmal expansion in both fibrillin-1 hypomorphic mice and those chronically infused with AngII. These studies reported increased incidence of aortic dissection and rupture in both abdominal and thoracic regions. The role of TGF-b deficiency has also been studied, but the low postnatal viability of mice deficient in its different isoforms is a barrier to defining the effect on aortic diseases. One study has demonstrated augmented aortic root aneurysms in both TGF-b2 heterozygous deficient and fibrillin-1 haploinsufficient mice. Although these mice demonstrated The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Saha Cardiovascular Research Center (A.D., M.B.S., Z.C., H.S., D.L.R.), Departments of Physiology (A.D., Z.C.), Family Medicine (M.B.S.), and Surgery (M.B.S.), University of Kentucky, Lexington, KY. Correspondence to: Alan Daugherty, PhD, DSc, Saha Cardiovascular Research Center, University of Kentucky, B243 Biomedical Biological Sciences Research Bldg, Lexington, KY 40536. E-mail: [email protected] J Am Heart Assoc. 2017;6:e005221. DOI: 10.1161/JAHA.116.005221. a 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.