The inflammasome adaptor ASC mediates pulmonary artery remodelling

Background: Inflammasomes are large multiprotein oligomers consisting of a receptor (such as NLRP3), the adaptor protein (ASC) and caspase-1. Assembly of the inflammasome activates caspase-1 which cleaves interleukin (IL)-18 and IL-1β to their bioactive forms. Elevated levels of IL-18 and IL-1β are found in patients with pulmonary hypertension, and increased levels of IL-18 have been found in alveolar hypoxia which leads to pulmonary hypertension. Objective: To study the role of ASC in chronic hypoxia-induced pulmonary artery remodelling. Methods: WT, NLRP3 -/- and ASC -/- mice were exposed to 3 months of hypoxia in a tightly sealed chamber containing 10% oxygen. Right ventricular systolic pressure (RVSP) was measured with a microtipped transducer catheter. To quantify muscularization and collagen content of arteries, lung sections were stained with von Willebrand factor, smooth muscle α-actin, acid fuchsin orange G-stain (AFOG) and Sirius Red. Results: ASC -/- mice exposed to hypoxia had significantly lower RVSP than WT hypoxic mice, indicating reduced pulmonary hypertension. RVSP of NLRP3 -/- exposed to hypoxia was not altered compared to WT hypoxia. Hypoxic ASC -/- mice showed less degree of muscularization and fibrosis around pulmonary arteries compared to WT mice exposed to hypoxia. Conclusions: Depletion of the inflammasome adaptor ASC diminish pulmonary artery remodelling in hypoxia-induced pulmonary hypertension.