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

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.

SU5416 plus hypoxia but not selective VEGFR2 inhibition with cabozantinib plus hypoxia induces pulmonary hypertension in rats: potential role of BMPR2 signaling

“…However, gene expression of TGFRb2 was not different in the SU5416H vs. control groups. The gene expression results from Sanada et al 23 are thus similar to the results of our Nanostring analyses in this regard, and highlight the recognition that changes in gene expression or absence thereof do not necessarily reflect protein levels and consequent effects on signaling. The apparent discrepancies between changes in protein levels and gene expression also highlight the importance of localized regulation in the microenvironment of pulmonary vascular lesions.…”

“…20– 22 Sanada et al. 23 recently examined TGF and SMAD levels in human PAH as well as animal models of PAH. By immunofluorescent staining, TGFRb1 was not different in the SU5416H model vs. controls, but TGFRb2 was increased in pulmonary vessels.…”

“…Loss of function SMAD9 mutations have been reported as an infrequent cause of PAH and restoration of SMAD9 functioning could decrease proliferation of PAH smooth muscle cells. [20][21][22] Sanada et al 23 recently examined TGF and SMAD levels in human PAH as well as animal models of PAH. By immunofluorescent staining, TGFRb1 was not different in the SU5416H model vs. controls, but TGFRb2 was increased in pulmonary vessels.…”

N7-methylguanosine modification of lncRNAs in a rat model of hypoxic pulmonary hypertension: a comprehensive analysis

“…Analysis of the differentially expressed m7G lncRNAs revealed an overlap of 11 pseudogenes between the identified lncRNAs. Among the overlapped pseudogenes, Smad3 is a key downstream element in transforming growth factor (TGF)-β signaling pathways [33]. In recent years, the critical role of TGF-β signaling pathways in PH has been better elucidated.…”

Inhibition of the prolyl isomerase Pin1 improves endothelial function and attenuates vascular remodelling in pulmonary hypertension by inhibiting TGF-β signalling

“…The abnormal pulmonary vascular remodelling is characterized by a hyperproliferative, apoptosis-resistant and inflammatory phenotype of pulmonary arterial endothelial cells (PAECs) and smooth muscle cells (SMCs) [5][6][7][8][9]. The pathophysiologic mechanism involves several signalling pathways, including the TGF-β/BMP pathway [10][11][12][13]. Despite recent advances in the molecular understanding of the vascular remodelling in PAH, current therapies fail to reverse this vascular remodelling, resulting in only a modest improvement in morbidity and mortality.…”