Abstract 18780: Down-regulation of BMPR2 in Pulmonary Hypertension Secondary to Lung Fibrosis
Pulmonary Hypertension (PH) is a disorder affecting the vasculature of the lung. A highly prevalent form of PH is that associated with underlying chronic lung diseases such as chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF). However, little is known about the mechanisms that drive the development of PH secondary to chronic lung diseases. Loss of function mutations in bone morphogenic protein receptor (BMPR) 2 have been strongly linked to familial and non-familial cases of pulmonary arterial hypertension (PAH). In PAH, loss of function BMPR2 mutations lead to pronounced vascular remodeling and increased responsiveness of vascular smooth muscle cells to the pro-fibrotic cytokine, transforming growth factor (TGF)-β. In addition, the loss of BMPR2 function in vascular smooth muscle cells abrogates the anti-proliferative effects of BMP ligands by altering downstream Smad signaling pathways. Our hypothesis is that BMPR2 is down-regulated in PH secondary to lung fibrosis.
Using human lung explant samples from patients with IPF and PH secondary to IPF, as well as normal control tissue, we report a down-regulation of BMPR2 expression in patients with IPF compared to normal controls and a further down-regulation of BMPR2 expression in patients with IPF + PH compared to patients with IPF but no PH. These changes were consistent with altered Smad phosphorylation showing dampened P-Smad 1/5/8 and elevated P-Smad 2/3 in tissues from patients with IPF and PH suggestive of reduced BMPR2 signaling and elevated TGF-β activity. In addition, pulmonary artery smooth muscle cells (PASMCs) from patients with PH secondary to COPD presented with reduced BMPR2 expression compared to normal controls that was further down-regulated by hypoxia. In an animal model of PH secondary to lung fibrosis, we also report decreased BMPR2 expression compared to control animals that correlated with vascular remodeling and PH. In conclusion, our data suggest that loss of function of BMPR2 may be a mechanism leading to PH secondary to lung fibrosis.
Author Disclosures: N. Chen: None. T. Weng: None. L.J. Garcia Morales: None. H. Karmouty Quintana: None.
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.