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Elucidating how mutations in EIF2AK4 cause pulmonary vascular disease



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Schwiening, Max Henry 


Pulmonary veno-occlusive disease (PVOD) is an incurable condition characterised by the progressive remodelling of pulmonary veins, venules and capillaries. This obstruction of the pulmonary vessels causes increased pulmonary pressures which leads to right ventricular hypertrophy, and death within 1-2 years if untreated. Biallelic mutations in the stress sensing kinase, EIF2AK4 (GCN2), are the main genetic cause of PVOD. I hypothesised that loss of GCN2 may lead to a pro-inflammatory phenotype which could be contributing to the development of PVOD. PVOD was modelled using mice with homozygous null mutations in gcn2. Gcn2-/- mice spontaneously developed an increase in right ventricular systolic pressure, compared to wild-type controls (28.1 ± 3.4 vs. 24.7 ± 3.7 mmHg, p = 0.04). Both left and right ventricles exhibited hypertrophy in the gcn2-/- mice but left ventricular systolic pressures were normal. Inflammatory cytokines, in particular interleukin 6, were raised in gcn2-/- mice at baseline in both serum and lung compartments which was exaggerated after stimulation with LPS. Chronic exposure to LPS in gcn2-/- mice led to elevated right ventricular systolic pressures which was prevented by genetic deletion of interleukin 6. Since the chemotherapy drug mitomycin-c can also induce PVOD in humans I decided to create an orthogonal model of PVOD by exposing wild-type mice to mitomycin-c. These mice also demonstrated right ventricular remodelling, which was prevented by genetic ablation of interleukin 6. Preliminary single-cell RNA sequencing analysis of lung cells from gcn2-/- mice shows potential upregulation of pro-inflammatory pathways in gcn2-/- macrophages and fibroblasts. I have shown, for the first time, that gcn2-/- mice at baseline reproduce features of PVOD and share a pro-inflammatory phenotype with other forms of pulmonary hypertension and these are prevented by loss interleukin 6.





Marciniak, Stefan
Soon, Elaine


Cardiac, EIF2AK4, GCN2, Mouse, Pulmnonary arterial hypertension, Pulmonary, Pulmonary hypertension


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
Medical Research Council (MR/R008051/1)
MRC (MR/W029251/1)