Noncanonical TGFβ Signaling Contributes to Aortic Aneurysm Progression in Marfan Syndrome Mice

Abstract

Transforming growth factor–β (TGFβ) signaling drives aneurysm progression in multiple disorders, including Marfan syndrome (MFS), and therapies that inhibit this signaling cascade are in clinical trials. TGFβ can stimulate multiple intracellular signaling pathways, but it is unclear which of these pathways drives aortic disease and, when inhibited, which result in disease amelioration. Here we show that extracellular signal–regulated kinase (ERK) 1 and 2 and Smad2 are activated in a mouse model of MFS, and both are inhibited by therapies directed against TGFβ. Whereas selective inhibition of ERK1/2 activation ameliorated aortic growth, Smad4 deficiency exacerbated aortic disease and caused premature death in MFS mice. Smad4-deficient MFS mice uniquely showed activation of Jun N-terminal kinase–1 (JNK1), and a JNK antagonist ameliorated aortic growth in MFS mice that lacked or retained full Smad4 expression. Thus, noncanonical (Smad-independent) TGFβ signaling is a prominent driver of aortic disease in MFS mice, and inhibition of the ERK1/2 or JNK1 pathways is a potential therapeutic strategy for the disease.

Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma

“…TGFb, a central molecule in the pathogenesis of Marfan aortopathy 12,14,[32][33][34] , and its downstream signalling pathways (canonical pSmad2 (ref. 35) and non-canonical pERK1/2 (ref.…”

“…Recent advancements in understanding mechanisms of aortic disease have stemmed from hallmark studies in the genetically fragile Marfan aorta, which have shown that transforming growth factor b (TGFb) and its downstream intracellular kinase signalling pathways play a central role in the pathogenesis [12][13][14] . In contrast, an inflammatory pathway is thought to be a major component of aortic conditions in the atherosclerotic/ degenerative aorta seen in the typical elderly patient 15,16 .…”

The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen–Goldberg syndrome

“…1,2 During the last decade, it has become increasingly clear that dysregulated transforming growth factor beta (TGFb) signaling is having a major role in the pathogenesis of MFS, LDS, and related disorders involving thoracic aortic aneurysms. [3][4][5][6][7][8][9] Because of the overlap with MFS and LDS and because several lines of evidence have confirmed a key role of TGFb signaling in the pathogenesis of MFS and LDS, it was hypothesized that altered TGFb signaling also underlies the SGS pathogenesis. Indeed, de novo, heterozygous mutations in SKI (Sloan-Kettering Institute), encoding a known repressor of TGFb signaling, were identified in 10 SGS patients.…”

Congenital Heart Disease: In Search of Remedial Etiologies

“…In patients with Down, Marfan, or Noonan Syndromes, there is increasing evidence that genes encoding nodal signaling kinases like FAK/AKTkt/PI3K, RAS, MEKK/ ERK1/2, PTPN11, etc., are likely candidates for CHD if they are mutated or overexpressed [2][3][4]. Such genes are not usually lethal (as there exist molecular or functional redundancies), yet as indicated for syndromic heart defects, they have potential to change functional behaviors in progenitor cells that normally mold and remodel the simple tubular heart into a four-chambered organ.…”

“…The evolution of genetic thought is toward trans-heterozygous, multigenetic interactions vs. single gene hits. 3. Mutations in the downstream intracellular signaling targets of growth factor, transcription factors, or matricellular proteins are more likely to be the root cause of heart defects seen in children by pediatric cardiologists (as the loss of both alleles for upstream early regulatory genes is usually lethal).…”