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Altered TGFβ/SMAD Signaling in Human and Rat Models of Pulmonary Hypertension: An Old Target Needs Attention

Recent translational studies highlighted the inhibition of transforming growth factor (TGF)-β signaling as a promising target to treat pulmonary arterial hypertension (PAH). However, it remains unclear whether alterations in TGF-β signaling are consistent between PAH patients and animal models. Therefore, we compared TGF-β signaling in the lungs of PAH patients and rats with experimental PAH induced by monocrotaline (MCT) or SU5416+hypoxia (SuHx). In hereditary PAH (hPAH) patients, there was a moderate increase in both TGFβR2 and pSMAD2/3 protein levels, while these were unaltered in idiopathic PAH (iPAH) patients. Protein levels of TGFβR2 and pSMAD2/3 were locally increased in the pulmonary vasculature of PAH rats under both experimental conditions. Conversely, the protein levels of TGFβR2 and pSMAD2/3 were reduced in SuHx while slightly increased in MCT. mRNA levels of plasminogen activator inhibitor (PAI)-1 were increased only in MCT animals and such an increase was not observed in SuHx rats or in iPAH and hPAH patients. In conclusion, our data demonstrate considerable discrepancies in TGFβ-SMAD signaling between iPAH and hPAH patients, as well as between patients and rats with experimental PAH.

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S2845 Semaxanib (SU5416) Semaxanib (SU5416, semaxinib) is a potent and selective VEGFR(Flk-1/KDR) inhibitor with IC50 of 1.23 μM, 20-fold more selective for VEGFR than PDGFRβ, lack of activity against EGFR, InsR and FGFR. Phase 3.Semaxanib (SU5416) can be used to induce animal models of chronic intermittent hypoxia.

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VEGFR