Abstract 19602: Characterization of Tgfβ/BMP-axis in Multiple Animal Models of PH

Abstract

Introduction: Mutations in the bone morphogenetic protein recptor type 2 (BMPR2) comprise a large portion of familial Pulmonary Arterial Hypertension (PAH) cases. The transforming growth factor-β (TGF-β)/BMP-axis in PAH has been of interest, which is hypothesized to favor TGF-β signaling due to defective BMPR2 signaling, consequently leading to pro-proliferative signaling within the lung. In addition, it has been proposed that the BMPRII mutations might affect cardiac adaptation. To date none of the available animal models have been fully characterized with regard to the TGF-β/BMP pathway. This study assessed the lung and heart TGF-β/BMP-axis in multiple rat animal models of pulmonary hypertension to ensure translational capability. Methods: Heart and lung TGF-β/BMP-axis was assessed by qPCR, western blot and immunofluorescence in the the monocrotaline (MCT), Sugen-hypoxia (SuHx), Sugen-Pneumonectomy (SuPnx) and Pulmonary artery banding model (PAB) and compared to control and PAH patient tissues. Circulating ligands, TGF-β receptor (TGFβR) type 1 and 2 and BMPR2, and canonical downstream signaling (Smad2/3, Smad1/5/8, and transcription factors) were investigated. Results: BMPR2 was down-regulated at both transcription and protein levels in the lung of all PH animal models (p<0.05). Transcription of pulmonary TGFβR1 and -2 were increased in the SuPNx-model, compared to control (P<0.001). In both SuHx and SuPnx models an increase in protein Smad2/3 expression was observed by immunofluorescence implying overactivation of TGF-β signaling. Cardiac TGFβR1 was decreased in PAB model, compared to control (P<0.05), while TGFβR2 was decreased in both the MCT and PAB model. Conclusion: Early indications reveal differences between several pulmonary hypertension animal models, with regard to the TGF-β/BMP pathway. Additional analysis is needed to fully characterize the regulation of TGF-β and BMP in the rat models.