Links between dysfunctional Bone Morphogenetic Protein signalling and Interleukin-1ß mediated inflammation in pulmonary arterial hypertension

Rationale: Bone morphogenetic protein receptor type 2 (BMPR2) mutations are present in up to 70% of patients with heritable and up to 25% with idiopathic pulmonary arterial hypertension, however penetrance within families with the same mutation is low implying the necessity for a ‘second hit’. Inflammatory cytokines are raised in patients with PAH, and in animal models have been shown to play a modulating role in disease pathogenesis. Objective: To determine whether there is a pulmonary specific interplay between BMPR2 deficiency and inflammatory Interleukin 1ß (IL-1ß) signalling that may explain the local manifestation of PAH in the lung. Methods and Results: mRNA microarray analysis of RNA isolated from pulmonary artery (PASMC) and aortic (AoSMC) smooth muscle cells demonstrated reduced inflammatory pathway activation in response to IL-1ß in PASMC compared with AoSMCs. However, further microarray analysis of PASMCs analysis demonstrated an exaggerated inflammatory response to IL-1ß upon loss of BMPR2 signalling. To determine whether IL-1ß supplementation would exacerbate disease phenotype on the background of a BMPR2 mutation, R899X+/- BMPR2 transgenic mice fed western diet for six weeks were given daily injections of IL-1ß. IL-1ß treated mice had higher white blood cell counts, demonstrating effective administration of IL-1ß. Raised serum protein levels of Interleukin-6 and Osteoprotegerin recapitulating in vitro PASMC data. Phenotypically, IL-1ß treated mice demonstrated a significant increase in pulmonary vascular remodelling. Conclusion: IL-1ß induces a pulmonary artery-specific transcriptome that is altered by suppression of BMPR2 signalling in vitro. In vivo and in vitro IL-1ß drives an exaggerated inflammatory response under conditions where BMPR2 signalling is reduced