Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics
Session Type: Abstract Submissions (ACR)
Background/Purpose
Scleroderma patients are susceptible to development of pulmonary arterial hypertension (PAH) that has similarities to some forms of heritable PAH. The basis for this susceptibility is unclear and SSc-PAH has a worse clinical outcome. We have previously shown that a TGFβ dependent mouse model of scleroderma (TβRIIΔk-fib) develops PAH in response to pulmonary endothelial cell injury. Using this model as a platform and clinical material form SSc lungs we explored expression and proteasomal degradation of BMPRII that is implicated in development of heritable PAH.
Methods
We investigated BMP signalling in the lung in the TβRIIΔk-fib model of PAH-SSc in which TGFβ signalling is upregulated. The TβRIIΔk-fib mouse develops a structural pulmonary vasculopathy with smooth muscle hypertrophy and raised right ventricular pressures. Experiments were performed on whole lung isolates and explant cultured fibroblasts (n=6) from the TβRIIΔk-fib mouse and compared with wildtype controls. TGFβ/BMP signalling pathways were investigated by Western blot and immunohistochemistry and qPCR. MG132, an inhibitor of proteasomal degradation, was used to explore the role of proteasomal degradation on BMPRII protein levels in vitro.
Results
The TβRIIΔk-fib model has increased levels of pSmad2/3, indicative of enhanced TGFβ signalling. The TβRIIΔk-fib model exhibits a significant reduction in BMPRII protein expression in whole lung isolates (1.43, 0.38) (p<0.05), and explant cultured fibroblasts (0.299, 0.09) (p<0.05). A reduction of BMPRII was also observed in whole lung (0.095, 0.03) and explant cultured lung fibroblasts from SSc patients compared to healthy controls (p<0.05) but there was an increase in BMPRII gene expression. Interestingly, both TβRIIΔk-fib and SSc fibroblasts exhibited refractory responses to BMP4 (p<0.05). MG132 was able to restore BMPRII protein levels and restore BMP4 ligand response of SSc fibroblasts.
Conclusion
Here we demonstrate the TβRIIΔk-fib transgenic murine model of PAH-SSc exhibits reduced expression of BMPRII as a reciprocal response to increased TGFβ signalling. Collectively our data suggests loss of BMPRII expression by non-genetic means may contribute to the development of PAH in SSc. Further, our results suggest that use of a proteasomal degradation inhibitor might reduce the risk of developing PAH by restoring BMPRII expression.
Disclosure:
A. J. Gilbane,
None;
E. C. Derrett-Smith,
None;
A. Pearce,
None;
C. P. Denton,
None;
A. M. Holmes,
None.
ACR Meeting Abstracts - https://acrabstracts.org/abstract/increased-degradation-of-bmpr2-in-a-tgf%ce%b2-dependent-transgenic-mouse-model-of-scleroderma-with-susceptibility-to-pulmonary-arterial-hypertension/