Abstract 13921: Dysfunctional Bone Morphogenetic Protein Signaling Interlinks With Interleukin-1ß Mediated Inflammation in Pulmonary Arterial Hypertension
Rationale: Bone morphogenetic protein receptor type 2 (BMPR2) mutations are found in heritable and idiopathic pulmonary arterial hypertension but disease penetrance is incomplete implying the necessity for a ‘second hit’. IL-1ß and IL-6 are increased in PAH patients and animal models and are proposed to play a critical role in disease.
Objective: To determine pulmonary specific interplay between BMPR2 and IL-1ß signaling by exploring differences between pulmonary artery and aortic smooth muscle cells (PA / Ao SMC) in response to IL-1ß, and determine the effects of reduced BMPR2 expression using in vitro and in vivo disease models.
Methods and Results: Microarray analysis of PASMC and AoSMC mRNA show reduced inflammatory pathway activation in response to IL-1ß in PASMC compared with AoSMCs. Pathway analysis identified an exaggerated inflammatory response to IL-1ß in PASMC lacking BMPR2 (siRNA). Significant up-regulation of IL-6, IL-1α and adhesion molecules (>2-fold) shown by array analysis was validated by qPCR. In the absence of BMPR2 a 1.5-fold increase in proliferation was observed in response to IL-1ß that is not present in PASMC with functional BMPR2. To study this further, R899X+/- BMPR2 transgenic mice were fed western diet for six weeks and given daily injections of IL-1ß. Mice were assessed for inflammatory activation and PAH phenotype (catheter/echo). mRNA and protein changes were measured by TaqMan PCR, western blotting and serum ELISA. Mice treated with IL-1ß had significantly higher white blood cell counts (1.7-fold), and showed trends for increased mRNA of VCAM1, IL-1α (whole lung) and significantly raised serum protein levels of IL-6 and OPG matching in vitro data. IL-1ß treated mice had an increase in early pulmonary vascular remodelling and the full assessment of the inflammatory cell infiltrate in R899X+/- mice is currently underway.
Conclusion: IL-1ß induces a pulmonary artery specific transcriptome that is altered by suppression of BMPR2 signaling in vitro. In vivo and in vitro IL-1ß drives an exaggerated inflammatory response under conditions of reduced BMPR2 signaling. This research highlights a mechanism by which increased IL-1ß may provide a “second hit” to reduced BMPR2 signaling and stimulate or potentiate the development of PAH.
Author Disclosures: J.A. Pickworth: None. S. Shay: None. S. Gladson: None. J. Iremonger: None. A.M. Rothman: None. S. Francis: None. J. West: None. A. Lawrie: None.
- © 2015 by American Heart Association, Inc.