Paigen Diet–Fed Apolipoprotein E Knockout Mice Develop Severe Pulmonary Hypertension in an Interleukin-1–Dependent Manner

Inflammatory mechanisms are proposed to play a significant role in the pathogenesis of pulmonary arterial hypertension (PAH). Previous studies have described PAH in fat-fed apolipoprotein E knockout (ApoE−/−) mice. We have reported that signaling in interleukin-1–receptor–knockout (IL-1R1−/−) mice leads to a reduction in diet-induced systemic atherosclerosis. We subsequently hypothesized that double-null (ApoE−/−/IL-1R1−/−) mice would show a reduced PAH phenotype compared with that of ApoE−/− mice. Male IL-1R1−/−, ApoE−/−, and ApoE−/−/IL-1R1−/− mice were fed regular chow or a high-fat diet (Paigen diet) for 8 weeks before phenotyping for PAH. No abnormal phenotype was observed in the IL-1R1−/− mice. Fat-fed ApoE−/− mice developed significantly increased right ventricular systolic pressure and substantial pulmonary vascular remodeling. Surprisingly, ApoE−/−/IL-1R1−/− mice showed an even more severe PAH phenotype. Further molecular investigation revealed the expression of a putative, alternatively primed IL-1R1 transcript expressed within the lungs but not aorta of ApoE−/−/IL-1R1−/− mice. Treatment of ApoE−/− and ApoE−/−/IL-1R1−/− mice with IL-1–receptor antagonist prevented progression of the PAH phenotype in both strains. Blocking IL-1 signaling may have beneficial effects in treating PAH, and alternative IL-1–receptor signaling in the lung may be important in driving PAH pathogenesis