EXPRESS: Differential IL-1 signalling induced by BMPR2 deficiency drives pulmonary vascular remodelling

Background: Bone morphogenetic protein receptor type 2 (BMPR2) mutations are present in patients with heritable and idiopathic pulmonary arterial hypertension (PAH). Circulating levels of Interleukin-1 (IL-1) are raised in patients and animal models. Whether interplay between BMP and IL- 1 signalling can explain the local manifestation of PAH in the lung remains unclear. Methods: Cell culture, siRNA and mRNA microarray analysis of RNA isolated from human Pulmonary artery (PASMC) and Aortic (AoSMC) smooth muscle cells were used. R899X+/- BMPR2 transgenic mice fed western diet for six weeks were given daily injections of IL-1ß prior to assessment for PAH and tissue collection. Results: PASMC have reduced inflammatory activation in response to IL-1ß compared with AoSMCs, however PASMC with reduced BMPR2 demonstrated an exaggerated response. Mice treated with IL-1ß had higher white blood cell counts, and significantly raised serum protein levels of IL-6 and OPG plasma levels recapitulating in vitro data. Phenotypically, IL-1ß treated mice demonstrated increased pulmonary vascular remodelling. Conclusions: IL-1ß induces an exaggerated pulmonary artery specific transcriptomic inflammatory response when BMPR2 signalling is reduced.