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- W2228815274 abstract "Upregulated TGFβ signalling plays a key role in mediating congenital thoracic aortic aneurysms (TAA), and has been implicated in bicuspid aortic valve-associated TAA (BAV-TAA). TGFβ is normally stored within the extra-cellular matrix via sequestration proteins bound to the microfibrillar protein, fibrillin. TGFβ is released in response to changes in these sequestration proteins, allowing TGFβ to exert its signalling effects. We hypothesised that in BAV-TAA the upregulation of TGFβ signalling will pathologically alter effector molecule expression, causing matrix degradation and altered TGFβ sequestration. Immunohistochemistry was used to quantify protein expression in aortic tissue from 8 human BAV-TAA and 6 normal controls. In BAV-TAA, TGFβ expression was elevated in all layers (2.5:1; p<0.05), particularly in the adventitia (3.4:1; p<0.001). Microfibril-associated glycoprotein-1 (MAGP-1), which promotes TGFβ release, was elevated (2:1; p<0.03), while latent TGFβ binding protein-1 (LTBP-1), which promotes TGFβ sequestration, was decreased (0.3:1; p=0.03). Matrix metalloproteinase-2 (MMP-2) and MMP-9 expression was elevated (2.6:1; p<0.005, 1.5:1; p<0.05, respectively), and MMP-3 expression was decreased (0.5:1; p<0.05). Fibrillin-1 expression was not altered. The observed changes in TGFβ sequestration proteins will increase unbound TGFβ, leading to upregulation of downstream signalling. The elevated levels of MMP-2 and MMP-9 mediate pathological matrix remodelling, leading to aortic dilatation. The paradoxical decrease in MMP-3 may represent a compensatory mechanism that attempts to reduce overall pathological MMP activity, in order to limit damage to the aortic wall. In conclusion, in BAV-TAA excessive TGFβ signalling is potentiated by reduced TGFβ sequestration, causing extra-cellular matrix degradation by MMPs. This supports the rationale for the use of angiotensin II receptor blockers in BAV-TAA." @default.
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- W2228815274 date "2014-11-25" @default.
- W2228815274 modified "2023-09-23" @default.
- W2228815274 title "Abstract 15097: Altered TGFβ Signalling Effector Molecules Contribute to Bicuspid Aortic Valve-associated Thoracic Aortopathy" @default.
- W2228815274 doi "https://doi.org/10.1161/circ.130.suppl_2.15097" @default.
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