Abstract
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.
Highlights
Pulmonary arterial hypertension (PAH) is a fatal disease characterized by elevated pulmonary arterial pressures eventually leading to right heart failure and premature death [1]
There was no significant correlation between the increased RV systolic pressure (RVSP) and plasma Transforming growth factor (TGF)-β1 level in either of the rat models
The present study describes the expression levels of TGF-β receptors and their direct downstream signaling component pSMAD2/3 in lung tissue of PAH patients as well as in two established rat models of PAH (MCT and SuHx)
Summary
Pulmonary arterial hypertension (PAH) is a fatal disease characterized by elevated pulmonary arterial pressures eventually leading to right heart failure and premature death [1]. The kinase inhibition of TGF-β receptor 1 (TGFβR1) suppressed the abnormal proliferation of PASMCs and PAECs and improved hemodynamics and vascular remodeling in PAH animal models [11,12,13]. Sotatercept decreased the expression of plasminogen activator inhibitor (PAI)-1, a known target gene of the TGF-β pathway and suppressed the aggravation of hemodynamics and vascular remodeling in experimental animal models of PAH [14]. The authors report that sotatercept significantly improved pulmonary vascular resistance and 6-minute walk distance in PAH patients [15], the extent of alterations in TGF-β signaling by sotatercept was not completely known. Despite several previous studies, the impact of TGF-β signaling on PAH in patients and animal models is still unclear. It is important to understand this signaling in both PAH patients and animal models in detail
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