Abstract 3157: Fat Fed ApoE/IL-1R1 Double Deficient Mice Are Protected From Atherosclerosis but Develop Severe Pulmonary Hypertension
Pulmonary arterial hypertension (PAH) is a life threatening condition with high morbidity and poor life expectancy. Inflammatory mechanisms are proposed to play a significant role in disease progression, particularly PAH associated with other diseases e.g. systemic sclerosis. Previous studies have demonstrated that members of the interleukin family of inflammatory cytokines are upregulated in PAH; treatment of rats with the IL-1 receptor antagonist has been shown to protect against development of monocrotaline-induced PAH, and IL-6 over-expression has been show to induce PAH in mice. Our group has recently demonstrated that ApoE−/−/IL-1R1−/− mice have reduced diet-induced atherosclerosis, and lower systemic blood pressure compared to ApoE−/− mice on the same diet. Since fat fed ApoE−/− mice have been shown to develop pulmonary hypertension, we hypothesized that ApoE/IL-1R1−/− mice would exhibit a reduced PAH phenotype. ApoE−/− and ApoE/IL-1R1−/− were fed either regular chow or Paigen diet for 8 weeks prior to echocardiography, right and left heart cardiac catheterization and serum and tissue harvest to assess pulmonary hypertension phenotype. The Paigen-fed ApoE developed increases in right ventricular systolic pressure (RVSP) in line with published data. Surprisingly, the ApoE−/−/IL-1R1−/− mice exhibited higher pressures (mean 66 mmHg, P<0.05 n=5). This finding was matched by significant increases in right ventricular hypertrophy compared to chow fed controls. Analysis of lung sections by alpha smooth muscle actin immunohistochemistry also revealed muscularisation of the distal pulmonary arteries. We have previously reported that high serum levels of OPG are associated with PAH in humans; this increase also correlates with development of PAH in rat models (unpublished). The ApoE−/−fat-fed mice exhibited a 2-fold increase (p<0.001, n=9), and the ApoE−/−/IL-1R1−/− animals a 4-fold increase (p<0.0001, n=5) in serum OPG compared to chow fed controls. These studies further implicate IL-1 signalling in PAH and further support a role for OPG in PAH. Additional studies are underway to examine other key inflammatory pathways to examine whether they compensate for the lack of IL-1 signalling in this model, and so drive disease pathogenesis.