Abstract 16188: ALK1-Dependent Transforming Growth Factor-β Signaling in Patients With Thoracic Aortic Aneurysm
Background: Transforming growth factor-beta (TGFβ) signaling and phosphorylation of Smad2 has been implicated in thoracic aortic aneurysm (TAA) development in Marfan syndrome (MFS). However, whether altered TGFβ signaling occurs in TAAs arising from other etiologies remains unclear. TGFβ differentially stimulates intracellular pathways dependent on type I (TGFBRI, ALK1) and type II (TGFBRII) TGFβ receptor dimerization. Activation of TGFBRI results in the phosphorylation of Smad2, whereas the activation of ALK1 results in the phosphorylation of Smad1/5/8. This study examined the hypothesis that TGFβ signaling is activated in TAA patients from non-MFS etiologies.
Methods and Results: Aortic tissue was collected and homogenized from TAA patients with either bicuspid (BAV; n=30) or tricuspid (TAV; n=29) aortic valves. TGFβ signaling components (TGFBR1, ALK1, Smad2, phospho-Smad2, Smad1/5/8, phospho-Smad1/5/8) were assessed by immunoblotting. Results were expressed as a percent change of non-aneurysmal aortic specimens obtained from heart transplant donors (n=5; set at 100%). In TAA tissue from BAV and TAV patients (respectively), Smad2 (133±13%, 175±18%), Smad1/5/8 (347±58%, 471±72%), and phospho-Smad1/5/8 (151±17%, 349±65%) abundance was increased compared to normal aorta (p<0.05). Likewise, TGFβ receptors, TGFBR1 (1046±227%, 1965±428%) and ALK1 (142±15%, 200±37%) were elevated (p<0.05). As an index of receptor/pathway activation, the phospho-Smad2:TGFBR1 versus phospho-Smad1/5/8:ALK1 ratios were determined, and results demonstrated increased ALK1 receptor pathway activation in both BAV and TAV TAAs (Figure ).
Conclusions: These data demonstrate that the TGFβ signaling pathway is activated in TAAs from BAV and TAV etiologies. Interestingly, the pattern of activation suggests that the TGFβ signal is diverted from a TGFBR1-dependent pathway and directed toward an ALK1-dependent pathway, which may have implications in TAA development.
- © 2013 by American Heart Association, Inc.