Abstract 14757: Role Of Stat3 Signalling In Aneurysm Development
Autosomal dominant (AD) Hyper-IgE syndrome (HIES) is a rare deficiency arising from mutations in the Signal Transducer and Activator of Transcription 3 (STAT3) gene and characterized by recurrent infections, skeletal and connective tissue abnormalities. Interestingly, some case reports described aneurysm incidence in HIES patients without exploring molecular causes of this disease. We hypothesized that deficiency in STAT3 signalling is involved in aneurysm susceptibility in HIES patients. For this, we used mouse models of Angiotensin (Ang) II-induced aortic aneurysm formation/rupture, with or without inhibition of STAT3-dependent signalling, to gain insight into the mechanisms of vascular alterations. Our results showed that inhibition of STAT3 using chemical compound inhibitor (n=19) led to a significant increase (P=0.01) in the severity of Ang II-induced abdominal aortic aneurysms (AAA) compared to treatment with the vehicle (n=20). Moreover, we obtained similar results in mice over-expressing SOCS3 (endogenous STAT3 inhibitor) (n=19) compared with controls (n=13) (P<0.0001). Interestingly, using a neutralizing anti-TGF-β antibody in association with AngII, which increases aneurysm rupture in C57Bl/6, we observed a dramatic acceleration in vessel rupture (P<0.0001) in Tg-SOCS3 mice (n=23) in comparison with controls (n=16). Furthermore, transplantation of Tg-SOCS3 bone morrow cells to lethally-irradiated C57Bl/6 mice (n=10) accelerated aneurysm severity compared to reconstitution with control bone marrow (n=10) (P=0.05). Splenocytes from Tg-SOCS3 mice displayed enhanced inflammatory profile compared with controls as revealed by increased production of IL-12 and IL-1β (P<0.05). Thus, inhibition of STAT3 signalling in mice significantly increases the susceptibility to vascular aneurysm, suggesting a mechanistic link between dominant-negative STAT3 mutations and vascular abnormalities in AD-HIES patients.
- © 2011 by American Heart Association, Inc.