The pathogenesis of aortopathy in Marfan syndrome and related diseases

Abstract

Marfan syndrome is a systemic connective tissue disorder that is inherited in an autosomal-dominant pattern with variable penetrance. Although there are many clinical manifestations of this disease, the most life threatening are cardiovascular complications, including mitral valve prolapse and aortic root aneurysm. When the primary defect was discovered in the fibrillin-1 gene, it was hypothesized that mutations in fibrillin-1 resulted in a weakened and disordered elastic architecture. However, recent evidence has suggested that the Marfan syndrome is caused by more than just a disordered microfibril matrix. Interest was stimulated when it was discovered that fibrillin-1 mutations enhanced the release of sequestered latent transforming growth factor-beta, a well-described mediator of vascular remodeling. This article focuses on the pathophysiology of aortopathy in the Marfan syndrome and related diseases, with special emphasis on the role of transforming growth factor-beta in mediating the pathogenesis of this disease.

Figure 1. TGF-β signaling pathway

TGF-β can signal through both the classical pathway and the non-canonical pathway. Signaling through the classical pathway is initiated upon binding of ligand to the type II TGF-β receptor (TGF-βRII). The type II receptor is autophosphorylated, and recruits and transphosphorylates a type I receptor (TGF-βRI). The activated type I receptor in turn phosphorylates and activates a receptor-Smad (R-Smad). The R-Smad then binds the common co-Smad and translocates to the nucleus. Once in the nucleus, it binds transcriptional co-factors and forms an activated transcriptional complex capable of inducing transcription of profibrotic genes. In the non-canonical pathway, TRAF6 associates with the type-I TGF-β receptor (TGF-βRI). It recruits and activates TGF-β associated kinase-1 (TAK1), which in turn activates p38MAPK. The p38MAPK is able to activate an R-Smad independent of TGF-β receptor kinase activity. Alternatively, p38MAK can initiate a signaling cascade resulting in altered transcription through other mediators that lead to enhanced matrix degradation.